Corticotropin releasing factor antagonists

ABSTRACT

Corticotropin-releasing factor (CRF) antagonists having the formulae  
                 
 
     wherein the dashed lines, A, B, Y, Z, G, R 3 , R 4 , R 5 , R 6 , R 16  and R 17  are as defined in the application, and processes for preparing them. These compounds and their pharmaceutically acceptable salts are useful in the treatment disorders including CNS and stress-related disorders.

[0001] This application claims priority under 35 U.S.C. 119 (e) of U.S.Provisional Patent Application 60/176,611, filed Jan. 18, 2000.

BACKGROUND OF THE INVENTION

[0002] This invention relates to pyridines, pyrimidines, purinones,pyrrolopyrimidinones and pyrrolopyridinones, processes for preparingthem, pharmaceutical compositions containing them, and methods of usingthem to treat certain central nervous system (CNS) and other disorders.

[0003] CRF antagonists are mentioned in U.S. Pat. Nos. 4,605,642, issuedAug. 12, 1986, and 5,063,245, issued Nov. 5, 1991, referring to peptidesand pyrazolinones, respectively. CRF antagonists are also described inU.S. Pat. No. 5,962,479, issued Oct. 5, 1999. The importance of CRFantagonists is set out in the literature, Q., as discussed in U.S. Pat.No. 5,063,245, which is incorporated herein by reference. A recentoutline of the different activities possessed by CRF antagonists isfound in M. J. Owens et al., Pharm. Rev., Vol. 43, pages 425 to 473(1991), also incorporated herein by reference. Based on the researchdescribed in these two and other references, CRF antagonists areeffective in the treatment of a wide range of stress-related illnesses,such as depression, anxiety, headache, irritable bowel syndrome,inflammatory diseases, immune suppression, Alzheimer's disease,gastrointestinal diseases, anorexia nervosa, hemorrhagic stress, drugand alcohol withdrawal symptoms, drug addiction, infertility, headtrauma, stroke, and stress-induced infections in humans and animals. Theuse of CRF antagonists for treatment of Syndrome X has also beendescribed in U.S. patent application Ser. No. 09/696,822, filed Oct. 26,2000, and European Patent Application No. 00309441.4, filed Oct. 26,2000, which are also incorporated in their entireties herein byreference. Methods for using CRF antagonists to treat congestive heartfailure are described in U.S. Ser. No. 09/248,073, filed Feb. 10, 1999,now U.S. Pat. No. 6,043,260 (issued Mar. 28, 2000) which is alsoincorporated herein in its entirety by reference.

SUMMARY OF THE INVENTION

[0004] The present invention provides compounds of the form ula

[0005] and pharmaceutically acceptable salts thereof, wherein the dashedlines represent optional double bonds, with the proviso that when thedashed line in C G represent a double bond, then the dashed line inN(R₆)═C does not represent a double bond; and with the proviso that whenthe dashed line in N(R₆)═C represents a double bond, R₆ is absent informula III and the dashed line in C═G does not represent a double bond;

[0006] A is —CR₇ or N;

[0007] B is —NR₁R₂, —CR₁R₂R₁₁, —C(═CR₂R₁₂)R₁, —NHCHR₁R₂, —OCHR₁R₂,—SCHR₁R₂, —CHR₂OR₁, —CHR₁OR₂, —CHR₂SR₁, —C(S)R₂, —C(O)R₂, —CHR₂NR₁R₂,—CHR₁NHR₂, —CHR₁N(CH₃)R₂, or —NR₁₂NR₁R₂;

[0008] when the dashed line in C═G represents a double bond, then G ishydrogen, oxygen, sulfur, NH, or N(C₁-C₄ alkyl);

[0009] when the dashed line in C═G does not represent a double bond,then C═G is —C(H)(NH₂), CH₂, —C(H)(methoxy), —C(H)(ethoxy),—C(H)(O(C₃-C₄ alkyl)), —C(H)(halo), —C(H)(trifluoromethoxy),—C(H)(methyl), —C(H)(ethyl), —C(H)(C₃-C₄ alkyl), —C(H)(S(C₁-C₄ alkyl)),—C(C₁-C₄ alkyl)(C₁-C₄ alkyl), cyclopropyl, —C(H)(cyclopropyl),thiomethoxy, —C(H)(NH₂), —C(H)(NHCH₃), —C(H)(N(CH₃)₂), or—C(H)(trifluoromethyl);

[0010] wherein said cyclopropyl, methoxy, ethoxy, C₃-C₄ alkyl, and C₁-C₄alkyl groups of C═G may optionally be substituted by one OH, methoxy, ortrifluoromethoxy, or may optionally be substituted by from one to sixfluoro atoms;

[0011] Y is CH or N;

[0012] Z is NH, O, S, —N(C₁-C₂ alkyl), —NC(O)CF₃, or —C(R₁₃R₁₄), whereinR₁₃ and R₁₄ are each, independently, hydrogen, trifluoromethyl ormethyl, or one of R₁₃ and R₁₄ is cyano and the other is hydrogen ormethyl, or —C(R₁₃R₁₄) is a cyclopropyl group, or Z is nitrogen or CH andforms; a five or six membered heterocyclic ring fused with R₅, whichring optionally comprises two or three further hetero members selectedindependently from oxygen, nitrogen, NR₁₂, and S(O)_(m), and optionallycomprises from one to three double bonds, and is optionally substitutedwith halo, C₁-C₄ alkyl, —O(C₁-C₄ alkyl), NH₂, NHCH₃, N(CH₃)₂, CF₃, orOCF₃, with the proviso that said ring does not contain any —S—S—, —S—O—,—N—S—, or —O—O— bonds, and does not comprise more than two oxygen orS(O)_(m) heterologous members;

[0013] R₁ is —C(O)H, —C(O)(C₁-C₆ alkyl), —C(O)(C₁-C₆ alkylene)(C₃-C₈cycloalkyl), —C(O)(C₃-C₈ cycloalkylene)(C₃-C₈ cycloalkyl), —C(O)(C₁-C₆alkylene)(C₄-C₈ heterocycloalkyl), —C(O)(C₃-C₈ cycloalkylene)(C₄-C₈heterocycloalkyl), —C₁-C₆ alkyl, —C₃-C₈ cycloalkyl, —C₄-C₈heterocycloallkyl, —(C₁-C₆ alkylene)(C₃-C₈ cycloalkyl), -(C₃-C₈cycloalkylene)(C₃-C₈ cycloalkyl), —(C₁-C₆ alkylene)(C₄-C₈heterocycloalkyl), —(C₃-C₈ cycloalkylene)(C₄-C₈ heterocycloalkyl), or—O-aryl, or —O—(C₁-C₆ alkylene)-aryl; wherein said aryl, C₄-C₈heterocycloalkyl, C₁-C₆ alkyl, C₃-C₈ cycloallcyl, C₃-C₈ cycloalkylene,and C₁-C₆ alkylene groups may each independently be optionallysubstituted with from one to six fluoro and may each independently beoptionally substituted with one or two substituents R₈ independentlyselected from the group consisting of C₁-C₄ alkyl, —C₃-C₈ cycloalkyl,hydroxy, fluoro, chloro, bromo, iodo, CF₃, —O—(C₁-C₆ alkyl), —O—(C₃-C₅cycloalkyl), —O—CO—(C₁-C₄ alkyl), —O—CO—NH(C₁-C₄ alkyl),—O—CO—N(R₂₄)(R₂₅), —N(R₂₄)(R₂₅), —S(C₁-C₄ alkyl), —S(C₃-C6 cycloalkyl),—N(C₁-C₄alkyl)CO(C₁-C₄ alkyl), —NHCO(C₁-C₄ alkyl), —COO(C₁-C₄ alkyl),—CONH(C₁-C₄ alkyl), —CON(C₁-C₄ alkyl)(C₁-C₂ alkyl), CN, NO₂, —OSO₂(C₁-C₄alkyl), S⁺(C₁-C₆ alkyl)(C₁-C₂ alkyl), —SO(C₁-C₄ alkyl) and —SO₂(C₁-C₄alkyl); and wherein the C₁-C₆ alkyl, C₁-C₆ alkylene, C₅-C₈ cycloalkyl,C₅-C₈ cycloalkylene, and C₅-C₈ heterocycloalkyl moieties of R₁ mayoptionally independently contain from one to three double or triplebonds; and wherein the C₁-C₄ alkyl moieties and the C₁-C₆ alkyl moietiesof R₈ can optionally independently be substituted with hydroxy, C₁-C₄alkyl, amino, aryl, —CH₂-aryl, —C₃-C₅ cycloalkyl, or —O—(C₁-C₄ alkyl),and can optionally independently be substituted with from one to fivefluoro, and can optionally contain one or two double or triple bonds;and wherein each heterocycloalkyl group of R. contains from one to threeheteromoieties selected from oxygen, S(O)m, nitrogen, and NR₁₂;

[0014] R₂ is hydrogen, C₁-C₁₂ alkyl, C₃-C₈ cycloalkyl, C₄-C₈heterocycloalkyl, -(C₁-C₆ alkylene)(C₃-C₈ cycloalkyl), —(C₃-C₈cycloalkylene)(C₃-C₈ cycloalkyl), —(C₁-C₆ alkylene)(C₄-C₈heterocycloalkyl), —(C₃-C₈ cycloalkylene)(C₄-C₈ heterocycloalkyl), aryl,—(C₁-C₆ alkylene)aryl, or —(C₃-C₈ cycloalkylene)(aryl); wherein each ofthe foregoing R₂ groups may optionally be substituted with from onethree substituents independently selected from chloro, fluoro, and C₁-C₆alkyl, wherein one of said one to three substituents can further beselected from bromo, iodo, C₁-C₆ alkoxy, —OH, —O—CO—(C₁-C₆ alkyl),—O—CO—N(C₁-C₄ alkyl)(C₁-C₂ alkyl), —S(C₁-C₆ alkyl), —S(O)(C₁-C₆ alkyl),—S(O)₂(C₁-C₆ alkyl), S⁺(C₁-C₆ alkyl)(C₁-C₂ alkyl), CN, and NO₂; andwherein the C₁-C₁₂ alkyl, —(C₁-C₆ alkylene), —(C₅-C₈ cycloalkyl),—(C₅-C₈ cycloalkylene), and —(C₅-C₈ heterocycloalkyl) moieties of R₂ mayoptionally independently contain from one to three double or triplebonds; and wherein each heterocycloalkyl group of R₂ contains from oneto three heteromoieties selected from oxygen, S(O)m, nitrogen, and NR₁₂;

[0015] or where R₁ and R₂ are as in —NHCHR₁R₂, —OCHR₁R₂, —SCHR₁R₂,—CHR₁R₂ or —NR₁R₂, R₁ and R₂ of B may form a saturated 5- to 8-memberedring which may optionally contain one or two double bonds and in whichone or two of the ring carbons may optionally be replaced by an oxygen,S(O)_(m), nitrogen or NR₁₂; and which carbocyclic ring can optionally besubstituted with from 1 to 3 substituents selected from the groupconsisting of hydroxy, C₁-C₄ alkyl, fluoro, chloro, bromo, iodo, CF₃,—O—(C₁-C₄ alkyl), —O—CO—(C₁-C₄ alkyl), —O—CO—NH(C₁-C₄ alkyl),—O—CO—N(C₁-C₄ alkyl)(C₁-C₂ alkyl), —NH(C₁-C₄ alkyl), —N(C₁-C₂alkyl)(C₁-C₄ alkyl), —S(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)CO(C₁-C₄ alkyl),—NHCO(C₁-C₄ alkyl), —COO(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CON(C₁-C₄alkyl)(C₁-C₂ alkyl), CN, NO₂, —OSO₂(C₁-C₄ alkyl), —SO(C₁-C₄ alkyl), and—SO₂(C₁-C₄ alkyl), wherein one of said one to three substituents canfurther be selected from phenyl;

[0016] R₃ is methyl, ethyl, fluoro, chloro, bromo, iodo, cyano, methoxy,OCF₃, NH₂, NH(C₁-C₂ alkyl), N(CH₃)₂, —NHCOCF₃, —NHCH₂CF₃, S(O)_(m)(C₁-C₄alkyl), CONH₂, —CONHCH₃, CON(CH₃)₂, —CF₃, or CH₂OCH₃;

[0017] R₄ is hydrogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl, —(C₁-C₄alkylene)(C₃-C₅ cycloalkyl), —(C₃-C₅ cycloalkylene)(C₃-C₅ cycloalkyl),cyano, fluoro, chloro, bromo, iodo, —OR₂₄, C₁-C₆ alkoxy, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ alkylene)(C₃-C₅ cycloalkyl), —O—(C₃-C₅cycloalkylene)(C₃-C₅ cycloalkyl), —CH₂SC(S)O(C₁-C₄ alkyl), —CH₂OCF₃,—CF₃, amino, nitro, —NR₂₄R₂₅, —(C₁-C₄ alkylene)-OR₂₄, —(C₁-C₄alkylene)C₁, —(C₁-C₄ alkylene)NR₂₄R₂₅, —NHCOR₂₄, —NHCONR₂₄R₂₅, —C═NOR₂₄,—NHNR₂₄R₂₅, —S(O)_(m)R₂₄, —C(O)R₂₄, —OC(O)R₂₄, —C(O)CN, —C(O)NR₂₄R₂₅,—C(O)NHNR₂₄R₂₅, and —COOR₂₄, wherein the alkyl and alkylene groups of R₄may optionally independently contain one or two double or triple bondsand may optionally independently be substituted with one or twosubstituents R₁₀ independently selected from hydroxy, amino, —NHCOCH₃,—NHCOCH₂C₁, —NH(C₁-C₂ alkyl), —N(C₁-C₂ alkyl)(C₁-C₂ alkyl), —COO(C₁-C₄alkyl), —COOH, —CO(C₁-C₄ alkyl), C₁-C₆ alkoxy, C₁-C₃ thioalkyl, cyanoand nitro, and with one to four substituents independently selected fromfluoro and chloro;

[0018] R₅ is aryl or heteroaryf and is substituted with from one to foursubstituents R₂₇ independently selected from halo, C₁-C₁₀ alkyl, —(C₁-C₄alkylene)(C₃-C₈ cycloalkyl), —(C₁-C₄ alkylene)(C₄-C₈ heterocycloalkyl),—(C₃-C₈ cycloalkyl), —(C₄-C₈ heterocycloalkyl), —(C₃-C₈cycloalkylene)(C₃-C₈ cycloalkyl), —(C₃-C₈ cycloalkylene)(C₄-C₈heterocycloalkyl), C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, nitro, cyano,—NR₂₄R₂₅, —NR₂₄COR₂₅, —NR₂₄CO₂R₂₆, —COR₂₄, —OR₂₅, —CONR₂₄R₂₅,—CO(NOR₂₂)R₂₃, —CO₂R₂₆, —C═N(OR₂₂)R₂₃, and —S(O)_(m)R₂₃; wherein saidC₁-C₁₀ alkyl, C₃-C₈ cycloalkyl, (C₁-C₄ alkylene), (C₃-C₈ cycloalkyl),(C₃-C₈ cycloalkylene), and (C₄-C₈ heterocycloalkyl) groups can beoptionally substituted with from one to three substituents independentlyselected form C₁-C₄ alkyl, C₃-C₈ cycloalkyl, (C₁-C₄ alkylene)(C₃-C₈cycloalkyl), —(C₃-C₈ cycloalkylene)(C₃-C₈ cycloalkyl), C₁-C₄ haloalkyl,hydroxy, C₁-C₆ alkoxy, nitro halo, cyano, —NR₂₄R₂₅, —NR₂₄COR₂₅,NR₂₄CO₂R₂₆, —COR₂₄, —OR₂₅, —CONR₂₄R₂₅, CO₂R₂₆, —CO(NOR₂₂)R₂₅, and—S(O)_(m)R₂₃; and wherein two adjacent substituents of the R₅ group canoptionally form a 5-7 membered ring, saturated or unsaturated, fused toR⁵, which ring optionally can contain one, two, or three heterologousmembers independently selected from O, S(O)_(m), and N, but not any—S—S—, —O—O—, —S—O—, or —N—S— bonds, and which ring is optionallysubstituted with C₁-C₄ alkyl, C₃-C₈ cycloalkyl, —(C₁-C₄ alkylene)(C₃-C₈cycloalkyl), —(C₃-C₈ cyloalkylene)(C₃-C₈ cycloalkyl), C₁-C₄ haloalkyl,nitro, halo, cyano —NR₂₄R₂₅, NR₂₄COR₂₅, NR₂₄CO₂R₂₆, —COR₂₄, —OR₂₅,—CONR₂₄R₂₅, CO₂R₂₆, —CO(NOR₂₆)R₂₅, or —S(O)_(m)R₂₃; wherein one of saidone to four optional substituents R₂₇ can further be selected from—SO₂NH(C₁-C₄ alkyl), SO₂NH(C₁-C₄ alkylene)(C₃-C₈ cycloalkyl),-SO₂NH(C₃-C₈ cycloalkyl), —SO₂NH(C₃-C₈ cycloalkylene)(C₃-C₈ cycloalkyl),—SO₂N(C₁-C₄ alkyl)(C₁-C₂ alkyl), —SO₂NH₂, —NHSO₂(C₁-C₄ alkyl),—NHSO₂(C₃-C₈ cycloalkyl), —NHSO₂(C₁-C₄ alkylene)(C₃-C₈ cycloalkyl), and—NHSO₂(C3-C₈ cycloalkylene)(C₃-C₈ cycloalkyl); and wherein the alkyl,and alkylene groups of R₅ may independently optionally contain onedouble or triple bond;

[0019] R₆ is hydrogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, —(C₁-C₆alkylene)(C₃-C₈ cycloalkyl), or (C₃-C₈ cycloalkylene)(C₃-C₈ cycloalkyl),wherein said alkyl and cycloalkyl may optionally be substituted with onehydroxy, methoxy, ethoxy or fluoro group;

[0020] or, wherein the compound is a compound of formula II, R₆ and R₄can together form an oxo (═O) group or can be connected to form a 3-8membered carbocyclic ring, optionally containing one to three doublebonds, and optionally containing one, two, or three heterologous ringmembers selected from O, SO_(m), N, and NR₁₂, but not containing any—O—O—, —S—O—, —S—S—, or —N—S— bonds, and further optionally substitutedwith C₁-C₄ alkyl or C₃-C₆ cycloalkyl, wherein said C₁-C₄ alkylsubstituent may optionally contain one double or triple bond;

[0021] R₇ is hydrogen, methyl, fluoro, chloro, bromo, iodo, cyano,hydroxy, —O(C₁-C₂ alkyl) —O (cyclopropyl), —COO(C₁-C₂ alkyl), —COO(C₃-C₈cycloalkyl), —OCF₃, CF₃, —CH₂OH, or CH₂OCH₃;

[0022] R₇ is hydrogen, hydroxy, fluoro, ethoxy, or methoxy;

[0023] R₁₂ is hydrogen or C₁-C₄ alkyl;

[0024] R₁₆ and R₁₇ are each, independently, hydrogen, hydroxy, methyl,ethyl, methoxy, or ethoxy, except that R₁₆ and R₁₇ are not both methoxyor ethoxy;

[0025] or R₁₆ and R₁₇ together form an oxo (═O) group;

[0026] or R₁₆ and R₁₇ are connected to form a 3-8 membered carbocyclicring, optionally containing one to three double bonds, and optionallycontaining from one to three heterologous ring members selected from O,SO_(m), N, and NR₁₂, but not containing any —O—O—, —O—, —S—S—, or —N—S—bonds, and further optionally substituted with C₁-C₄ alkyl or C₃-C₆cycloalkyl, wherein said C₁-C₄ alkyl substituent may optionally containone double or triple bond;

[0027] R₂₂ is independently at each occurrence selected from hydrogen,C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₈cycloalkyl, (C₃-C₈ cycloalkylene)(C₃-C₈ cycloalkyl), and (C₁-C₄alkylene)(C₃-C₈ cycloalkyl);

[0028] R₂₃ is independently at each occurrence selected from C₁-C₄alkyl, C₁-C₄ haloalkyl, C₂-C₈ alkoxyalkyl, C₃-C₈ cycloalkyl, —(C₁-C₄alkylene)(C₃-C₈ cycloalkyl), —(C₃-C₈ cycloalkylene)(C3-C₈ cycloalkyl),aryl, —(C₁-C₄ alkylene)aryl, piperidine, pyrrolidine, piperazine,N-methylpiperazine, morpholine, and thiomorpholine;

[0029] R₂₄ and R₂₅ are independently at each occurrence selected fromhydrogen, —C₁-C₄ alkyl, C₁-C₄ haloalkyl, especially CF₃, —CHF₂, CF₂CF₃,or CH₂CF₃, —(C₁-C₄ alkylene)OH, -(C,-C₄ alkylene)—O—(C₁-C₄ alkyl),—(C₁-C₄ alkylene)—O—(C₃-C₅ cycloalkyl), C₃-C₈ cycloalkyl, —(C₁-C₄alkylene)(C₃-C₈ cycloalkyl), —(C₃-C₈ cycloalkylene)(C₃-C₈ cycloalkyl),—(C₄-C₈ heterocycloalkyl), —(C₁-C₄ alkylene)(C₄-C₈ heterocycloalkyl),—(C₃-C₈ cycloalkylene)(C₄-C₈ heterocycloalkyl), aryl, and —(C₁-C₄alkylene)(aryl), wherein the —C₄-C₈ heterocycloalkyl groups can eachindependently optionally be substituted with aryl, CH₂-aryl, or C₁-C₄alkyl, and can optionally contain one or two double or triple bonds; or,when R₂₄ and R₂₅ are as NR₂₄R₂₅, —C(O)NR₂₄R₂₅, —(C₁-C₄ alkylene)NR₂₄R₂₅,or —NHCONR₂₄R₂₅, then NR₂₄R₂₅ may further optionally form a 4 to 8membered heterocyclic ring optionally containing one or two furtherhetero members independently selected from S(O)_(m), oxygen, nitrogen,and NR₁₂, and optionally containing from one to three double bonds;

[0030] R₂₆ is independently at each occurrence selected from C₁-C₄alkyl, C₁-C₄ haloalkyl, C_(3-C) ₈ cycloalkyl, —(C₁-C₄ alkylene)(C₃-C₈cycloalkyl), —(C₃-C₈ cycloalkylene)(C₃-C₈ cycloalkyl), aryl, and —(C₁-C₄alkylene)(aryl); and

[0031] wherein each m is independently zero, one, or two, with theproviso that heterocycloalkyl groups of the compound of formula I, II,or III do not comprise any —S—S—, —S—O—, —N—S—, or —O—O— bonds, and donot comprise more than two oxygen or S(O)_(m) heterologous members.

[0032] In one embodiment, the invention provides compounds of formula Ior II, wherein R₄ is —NHCH₂CF₃, —CONHNH₂, —CONHNHCH₃. In anotherembodiment R₄ is —OCF₃ or fluoro. In another embodiment R₄ is —OCHF₂.

[0033] In another embodiment, the invention provides compounds offormula I or II, preferably formula I, wherein R₄ is —C(O)NR₂₄R₂₅ or—C(O)NHNR₂₄R₂₅. In a preferred embodiment, R₄ is —C(O)NR₂₄R₂₅. If R₄ is—C(O)NR₂₄R₂₅ or —C(O)NHNR₂₄R₂₅, then R₂₄ and R₂₅ are in a moreparticular embodiment selected independently from hydrogen and —C₁-C₄alkyl. In another embodiment, R₄ is —C(O)NH₂ or —C(O)NHCH₃. In anotherembodiment, R₄ is —C(O)N(CH₃)₂.

[0034] In another more particular embodiment, the invention provides acompound of formula I, or II, preferably I, as defined above, wherein R₄is —C(O)NHCH₂(C₃-C₅ cycloalkyl), —C(O)NH(C₃-C₅ cycloalkyl), —C(O)N(C₃-C₅cycloalkyl)₂, —C(O)NR₂₄R₂₅ wherein R₂₄ and R₂₅ form a 4, 5, or 6membered heterocyclic ring, —C(O)NH(C₄-C₈ heterocycloalkyl), or—C(O)NH(CH₂(C₄-C₈ heterocycloalkyl)).

[0035] In another embodiment, the invention provides a compound offormula I or II, preferably formula I, wherein R₄ is —(C₁-C₄alkylene)NR₂₄R₂₅. If R₄ is —(C₁-C₄ alkylene)NR₂₄R₂₅, then R₂₄ and R₂₅are in a more particular embodiment selected independently fromhydrogen, —C₁-C₄ alkyl, —(C₁-C₄ alkylene)(C₃-C₈ cycloalkyl), and C₃-C₈cycloalkyl.

[0036] In another embodiment, the invention provides a compound offormula I or II as defined above, wherein R₄ is —OCH₂(C₃-C₅ cycloalkyl),—O—(C₃-C₅ cycloalkyl), —SCH₂(C₃-C₅ cycloalkyl), or —S(C₃-C₅ cycloalkyl).

[0037] In another embodiments of the invention, a compound of formula Ior II, preferably I, as defined above, is provided, wherein R₄ is—COOCH₃. In another embodiment of the invention, a compound of formula Ior II, preferably I, is provided wherein R₄ is —COOCH₂CH₃.

[0038] Another embodiment of the invention provides compounds of formulaI or II, preferably I, as defined above, wherein R₄ is —OCH₃. In anotherembodiment of the invention, compounds of formula I or II are provided,wherein R₄ is —CH₃. In another embodiment, R₄ is —CH₂CH₃. In anotherembodiment R₄ is chloro. In another embodiment, R₄ is bromo.

[0039] In another embodiment, a compound of formula I or II, preferablyI, is provided, wherein R₄ is —CF₃.

[0040] In another embodiment, a compound of formula I or II, preferablyI, is provided, wherein R₄ is —CH₂OH.

[0041] In another embodiment, a compound of formula I or II, preferablyI, is provided, wherein R₄ is —CH₂OCH₃.

[0042] In another embodiment, a compound of formula I or II, preferablyI, is provided, wherein R₄ is —CH₂OCF₃.

[0043] In another embodiment of the invention, the compound of formula Ior II, preferably I, is as defined above, and R₄ is —SCH₃.

[0044] In another embodiment, a compound of formula I or II, preferablyI, is provided, wherein R₄ is S(O)CH₃.

[0045] In another embodiment, a compound of formula I or II, preferablyI, is provided, wherein R₄ is (O)₂CH₃.

[0046] In another embodiment, a compound of formula I or II, preferablyI, is provided, wherein R₄ is —C(O)CH₃.

[0047] In another embodiment, a compound of formula I or II, preferablyI, is provided, wherein R₄ is —NR₂₄R₂₅. Preferably, R₂₄ and R₂₅ are-C₁-C₄ alkyl or hydrogen. In a more particular embodiment, R₄ is —NH₂,—NHCH₃, or —N(CH₃)₂.

[0048] In another embodiment, a compound of formula I or II, preferablyI, is provided, wherein R₄ is —NO₂.

[0049] In another embodiment, a compound of formula I or II, preferablyI, is provided, wherein R₄ is —CH(OH)CH₃.

[0050] In another embodiment, a compound of formula I or II, preferablyI, is provided, wherein R₄ is —CN.

[0051] In another embodiment, the invention provides compounds offormula 1, II, or III as defined above, wherein B is —NRIR₂, or—NHCHR₁R₂. If B is —NR₁R₂, R₁ is preferably C₁-C₆ alkyl, C₃-C₈cycloalkyl, or —(C₁-C₆ alkylene)(C₃-C₈ cycloalkyl), more preferably—(C₁-C₆ alkylene)(C₃-C₈ cycloalkyl), and R₂ is preferably C₁-C₁₂ alkyloptionally containing from one to three double or triple bonds andoptionally substituted with from one three fluoro atoms. Preferably, Bis —N(CH₂-cyclopropyl)(CH₂CH₃) or —N(CH₂-cyclopropyl)(CH₂CF₃).

[0052] If B is —NHCHR₁R₂, then R₁ is preferably —C(O)H, —C(O)(C₁-C₆alkyl), or —C₁-C₆ alkyl, wherein said C₁-C₆ alkyl is optionallysubstituted with from one to six fluoro atoms or one or two R₈independently selected from —C₁-C₄ alkyl, hydroxy and —O—(C₁-C₆ alkyl),and R₂ is preferably —C₁-C₁₂ alkyl optionally containing from one tothree double or triple bonds and optionally substituted with from onethree substituents selected from fluoro and C₁-C₆ alkyl. Preferably, ifB is —NHCHR₁R₂, then R₁ is independently selected from —CH₂CH₃ and—CF₂CH₃, and R₂ is independently selected from —CH₂CH₃, —CF₂CH₃,—CH(OH)CH₃, —CH(OCH₃)CH₃, —C(OH)(CH₃)₂, and —C(O)CH₃. Preferably B is—NHCH(CH₂CH₃)₂, —NHCH(CH₂CH₃)(CF₂CH₃), —NHCH(CF₂CH₃)₂,—NHCH(CH(OH)CH₃)(CF₂CH₃), —NHCH(CH(OH)CH₃)(CH₂CH₃),—NHCH(CH(OCH₃)CH₃)(CH₂CH₃), —NHCH(C(O)CH₃)(CH₂CH₃),—NHCH(C(O)CH₃)(CF₂CH₃), —NHCH(C(OH)(CH₃)₂)(CH₂CH₃), or—NHCH(C(OH)(CH₃)₂)(CF₂CH₃).

[0053] More preferably, B is —N(CH₂-cyclopropyl)(CH₂CH₃),—NHCH(CH₂CH₃)₂, —NHCH(CH(OH)CH₃)(CF₂CH₃), —NHCH(CH(OH)CH₃)(CH₂CH₃),—NHCH(CH(OCH₃)CH₃)(CH₂CH₃), —NHCH(C(O)CH₃)(CH₂CH₃), or—NHCH(C(OH)(CH₃)₂)(CH₂CH₃).

[0054] In another embodiment of the invention, B is selected from—OCHR₁R₂, SCHR₁R₂, —CHR₁NHR₂, —CHR₁N(CH₃)R₂, —CHR₂OR₁, and -CHR₁OR₂.

[0055] In another embodiment of the invention, a compound of formula I,II, or III as defined above is provided, wherein R₃ is methyl, ethyl,O—CH₃, —OCF₃, Cl, S—CH₃, or CF₃Preferably R₃ is methyl.

[0056] In another embodiment of the invention, a compound of formula IIIas defined above is provided wherein the dashed line in C═N(R₆)represents a double bond, and the dashed line in C═G does not representa double bond, and C═G is CH₂, C(H)(CH₃), or C(H)(CH₂CH₃).

[0057] In another embodiment of the invention, a compound of formula IIIis provided, wherein the dashed line in C═G represents a double bond,and C═G is C═O, C═S, or C═NH, and C═N(R₆) is C—NH or C—N(C₁-C₄ alkyl).

[0058] In another embodiment of the invention, a compound of formula IIas defined above is provided, wherein CR₁₆R₁₇ and CR₄R₆ are eachindependently selected from —C═O, —CH₂, —CH(C₁-C₄ alkyl), —C(C₁-C₂alkyl)₂, cyclopropyl, —CHOH, —CHOCH₃, —C(OCH₂CH₂), and —C(CH₂OCH₂).

[0059] In another embodiment, a compound of formula II is provided,wherein CR₁₆R₁₇ is selected from —CH₂, —CH(C₁-C₄ alkyl), —C(C₁-C₂alkyl)₂, cyclopropyl, —CHOH, and —CHOCH₃, and CR₄R₆ is C═O, CH₂,CH(C₁-C₂ alkyl), or —CHOCH₃

[0060] In another embodiment of the invention, a compound of formula I,II, or III as defined above is provided, wherein R₅ is optionallysubstituted aryl or heteroaryl selected from optionally substitutedphenyl, thiazolyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl,quinazolinyl, quinoxalinyl, pyrazinyl, pyrimidinyl, indazolyl,imidazolyl, furanyl, benzimidazolyl, benzofuranyl, benzothiazolyl,benzisoxazolyl, isothiazolyl, pyrazolyl, pyrrolyl, indolyl,pyrrolopyridyl, oxazolyl, benzoxazolyl, benzothiadiazolyl, pyridyl,benzo[1,3]dioxolyl, and 2,3-dihydro-benzo[1,4]dioxinyl.

[0061] In another embodiment, R₅ is substituted with from one to fourR₂₇ selected independently from C₁-C₄ alkyl, —O—(C₁-C₄ alkyl), chloro,bromo, —CH(CH₃)(OH), —C(CH₃)₂(OH), —CH(CH₃)(OCH₃), —C(CH₃)₂(OCH₃), OCF₃,OCHF₂, —O-cyclopropyl, —(—CH₂-cyclopropyl, —CH(CF₃)(OH), —CH(CF₃)(OCH₃),—C(═O)(CF₃), —2-cyclopropyl-1-OH, 1-cyclopropyl-2-OH,-1-cyclopropyl-1-NH₂, —O-oxetanyl, —O-tetrahydrofuranyl, cyclopropyl,and —SCH₃.

[0062] In another embodiment of the invention, a compound of formula I,II, or III as defined above is provided, wherein R₅ is phenyl, pyridylor pyrimidyl, substituted with two or three R₂₇ groups. In a moreparticular embodiment, R₅ is phenyl, substituted with two or three R₂₇groups.

[0063] In another embodiment, a compound of formula I, II or III,preferably I, as defined above is provided, wherein R₅ is phenyl,pyridyl or pyrimidyl, substituted with two or three R₂₇ groups selectedfrom halo, —(C₁-C₄ haloalkyl), —C(O)R₂₄, —OR₂₅, —C(O)NR₂₄R₂₅, and C₁-C₁₀alkyl which is optionally substituted with one to three substituents,preferably one substituent, selected from hydroxy, C₁-C₆ alkoxy, and—NR₂₄R₂₅. Preferably, each R₂₇ is independently selected from methyl,ethyl, —CF₃, —OCH₃, —OCF₃, —C(O)NH₂, —C(O)NHCH₃, —C(O)CF₃, —C(O)CH₃,—CH(OH)CH₃, chloro, bromo, fluoro, —OCH₂CH₃, —O-cyclopropyl, —CH₂NH₂,—CH₂NHCH₃, —CH₂N(CH₃)₂, —CH₂OCH₃, and —CH(OCH₃)CH₃. More preferably,each R₂₇ is independently selected from methyl, ethyl, —CF₃, —OCH₃,—OCF₃, —C(O)NH₂, —C(O)NHCH₃, chloro, bromo, and fluoro.

[0064] In another embodiment, a compound of formula I, II or III,preferably I, is provided, wherein—is phenyl and is substituted with twoor three substituents R₂₇ independently selected from methyl, chloro,—OCH₃, —OCF₃, bromo, and —C(O)NH₂.

[0065] In another embodiment of the invention, a compound of formula Ias defined above is provided, wherein Z is O, NH, or NC(═O)CF₃.Preferably Z is O.

[0066] In a preferred embodiment of the invention, a compound of formulaI is provided, wherein Z is O; B is —NHCHR₁R₂, wherein R₁ is preferably—C(O)H, —C(O)(C₁-C₆ alkyl), or —C₁-C₆ alkyl, wherein said C₁-C₆ alkyl isoptionally substituted with from one to six fluoro atoms or one or twoR₈ independently selected from —C₁-C₄ alkyl, hydroxy and ——(C₁-C₆alkyl), and wherein R₂ is preferably —C₁-Cl₂ alkyl optionally containingfrom one to three double or triple bonds and optionally substituted withfrom one three substituents selected from fluoro and C₁-C₆ alkyl; R₅ isR₅ is phenyl, pyridyl or pyrimidyl, substituted with two or three R₂₇groups selected from halo, —(C₁-C₄ haloalkyl), —C(O)R₂₄, —OR₂₅,—C(O)NR₂₄R₂₅, and C₁-C₁₀ alkyl which is optionally substituted with oneto three substituents, preferably one substituent, selected fromhydroxy, C₁-C₆ alkoxy, and —NR₂₄R₂₅; and R₄ is -C(O)NR₂₄R₂₅. R₂₄ and R₂₅of —C(O)NR₂₄R₂₅ are in a more particular embodiment selectedindependently from hydrogen and —C₁-C₄ alkyl.

[0067] In another preferred embodiment of the invention, a compound offormula I is provided, wherein Z is O; B is —NHCHR₁R₂, wherein R₁ of—NHCHR₁R₂ is preferably —C(O)H, —C(O)(C₁-C₆ alkyl), or —C₁-C₆ alkyl,wherein said C₁-C₆ alkyl is optionally substituted with from one to sixfluoro atoms or one or two R₈ independently selected from —C₁-C₄ alkyl,hydroxy and —O—(C₁-C₆ alkyl), and wherein R₂ of —NHCHR₁R₂ is preferably—C₁-C₁₂ alkyl optionally containing from one to three double or triplebonds and optionally substituted with from one three substituentsselected from fluoro and C₁-C₆ alkyl; R₅ is R₅ is phenyl, pyridyl orpyrimidyl, substituted with two or three R₂₇ groups selected from halo,—(C₁-C₄ haloalkyl), —C(O)R₂₄, —OR₂₅, —C(O)NR₂₄R₂₅, and C₁-C₁₀ alkylwhich is optionally substituted with one to three substituents,preferably one substituent, selected from hydroxy, C₁-C₆ alkoxy, and—NR₂₄R₂₅; and R₄ is —NR₁R₂, wherein R₁ of —NR₁R₂ is preferably C₁-C₆alkyl, C₃-C₈ cycloalkyl, or —(C₁-C₆ alkylene)(C₃-C₈ cycloalkyl), morepreferably —(C₁-C₆ alkylene)(C₃-C₈ cycloalkyl), and R₂ of —NR₁R₂ ispreferably C₁-C₁₂ alkyl optionally containing from one to three doubleor triple bonds and optionally substituted with from one three fluoroatoms. Preferably, B is —N(CH₂-cyclopropyl)(CH₂CH₃) or—N(CH₂-cyclopropyl)(CH₂CF₃).

[0068] Examples of preferred compounds of this invention are:

[0069]2-(4-Chloro-2,6-dimethyl-phenoxy)4-(1-hydroxymethyl-propylamino)-6,N-dimethyl-nicotinamide;

[0070] 2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-methoxymethyl-propylamino)-6,N-dimethyl-nicotinamide;

[0071]2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-methoxymethyl-propylamino)-6-methyl-nicotinamide;

[0072] 2-(4-Bromo-2-methoxy-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-nicotinamide;

[0073]2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-methoxy-propylamino)-6-methyl-nicotinamide;

[0074]2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-methoxy-propylamino)-6,N-dimethyl-nicotinamide;

[0075] 2-(4-Chloro-2-trifluoromethoxy-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-nicotinamide;

[0076] 2-(4-Chloro-2-trifluoromethoxy-phenoxy)-4-(1-ethyl-propylamino)-6-N-dimethyl-nicotinamide;

[0077]2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1S,2R-1-ethyl-2-methoxy-propylamino)-6,N-dimethyl-nicotinamide; and

[0078]2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1S,2S-1-ethyl-2-methoxy-propylamino)-6,N-dimethyl-nicotinamide;

[0079] and pharmaceutically acceptable salts thereof.

[0080] Other examples of preferred compounds of the invention are:

[0081]2-(4-Bromo-2-methoxy-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-nicotinonitrile;

[0082]4-[4-(1-Ethyl-propoxy)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-benzamide;

[0083] 2-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-4-(1-methylsulfanylmethyl-propylamino)-nicotinic acid methyl ester;

[0084]2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-methyl-nicotinicacid methyl ester;

[0085]2-(4-Bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-nicotinonitrile;

[0086]2-(4-Chloro-2-trifluoromethoxy-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-nicotinicacid methyl ester; and

[0087]2-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-4-(tetrahydro-furan-3-ylamino)-nicotinicacid methyl ester;

[0088] and pharmaceutically acceptable salts thereof.

[0089] Other examples of compounds of the invention are:

[0090]2-(4-bromo-2-methyl-phenylamino)-4-(1-ethyl-propoxy)-6-methyl-nicotinicacid;

[0091][2-(4-bromo-2-methyl-phenylamino)4-(1-ethyl-propoxy)-6-methyl-pyridin-3-yl]-methanol;

[0092]2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-methyl-nicotinicacid;

[0093]2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-methyl-nicotinamide;

[0094]2-(4-chloro-2,6-dimethyl-phenoxy)-N-ethyl-4-(1-hydroxymethyl-propylamino)-6-methyl-nicotinamide;

[0095]2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6,N-dimethyl-nicotinamide;

[0096]cyclopropylmethyl-[2,5,6-trimethyl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;

[0097]cyclopropylmethyl-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-amine;

[0098]2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-methoxycarbonyl-propylamino)-6-methyl-nicotinicacid methyl ester;

[0099]2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-methoxycarbonyl-propylamino)-6-methyl-nicotinicacid methyl ester;

[0100]3,3′,6′-trimethyl-2′-(2,4,6-trimethyl-phenoxy)-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl;

[0101]2-(4-chloro-2,6-dimethyl-phenoxy)-6,N-dimethyl-4-(S)-(tetrahydro-furan-3-ylamino)-nicotinamide;

[0102][7-(4-bromo-2,6-dimethyl-phenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-(tetrahydro-furan-3-yl)-amine;

[0103]2,5,6-trimethyl-4-pyrrolidin-1-yl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidine;

[0104](2-pyrrolidin-1-yl-ethyl)-[2,5,6-trimethyl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;

[0105](tetrahydro-furan-3-yl)-[2,5,6-trimethyl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine;

[0106]2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-4-(tetrahydro-furan-3-ylamino)-pyridine-3-carbaldehyde oxime;

[0107][3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl-(2-pyrrolidin-1-yl-ethyl)-amine;

[0108] N-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-2,2,2-trifluoro-N-(2-pyrrolidin-1-yl-ethyl)-acetamide;

[0109]N2-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-N1,N1-dimethyl-butane-1,2-diamine;

[0110]2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-methyiamino-propylamino)-6-methyl-nicotinicacid methyl ester;

[0111]6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(3-methyl-butyl)-(2-pyrrolidin-yl-ethyl)-amine;

[0112](3,3-dimethyl-butyl)-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(2-pyrrolidin-1-yl-ethyl)-amine;

[0113][3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-morpholin-4-y-amine;

[0114] 4-(-ethyl-propoxy)-2-(4-methoxy-2-methyl-phenylamino)-6-methyl-nicotinicacid;

[0115]2-(4-chloro-2-methyl-phenylamino)-4-(1-ethyl-propoxy)-6-methyl-nicotinicacid;

[0116]4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-pyridin-3-yloxy)-nicotinicacid;

[0117]N2-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin4-yl]-N1-pyridin-3-ylmethyl-butane-1,2-diamine;

[0118] N2-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-N1-thiazol-2-ylmethyl-butane-1,2-diamine;

[0119]2-(2,4-dimethyl-phenylamino)-4-(1-ethyl-propoxy)-6-methyl-nicotinicacid;

[0120][2-(4-chloro-2-methyl-phenylamino)-4-(1-ethyl-propoxy)-6-methyl-pyridin-3-yl]-methanol;

[0121]2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-methyl-nicotinonitrile;

[0122]1-(4-chloro-2-methyl-phenyl)-5-(1-ethyl-propoxy)-7-methyl-1,4-dihydro-2H-3-oxa-1,8-diaza-naphthalene;

[0123]4-(1-ethyl-propylamino)-2-methyl-7-(2,4,6-trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidine-5,6-dione;

[0124]4-(1-ethyl-propylamino)-2-methyl-7-(2,4,6-trimethyl-phenyl)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one;

[0125]4-[3-cyano-4-(1-ethyl-propylamino)-6-methyl-pyridin-2-yloxy]-3-methoxy-benzoicacid;

[0126] 2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-methoxymethyl-propylamino)-6-methyl-nicotinamide;

[0127] 2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-methoxymethyl-propylamino)-6,N-dimethyl-nicotinamide;

[0128] 2-(4-chloro-2,6-dimethyl-phenoxy)-N-(1-hydroxymethyl-propyl)-4-(1-hydroxymethyl-propylamino)-6-methyl-nicotinamide;

[0129] and pharmaceutically acceptable salts of the above compounds.

[0130] The invention also relates to a pharmaceutical composition forthe treatment of (a) a disorder or condition the treatment of which canbe effected or facilitated by antagonizing CRF, including but notlimited to disorders induced or facilitated by CRF, or (b) a disorder orcondition selected from inflammatory disorders such as rheumatoidarthritis and osteoarthritis, pain, asthma, psoriasis and allergies;generalized anxiety disorder; panic; phobias, including social phobia,agoraphobia, and specific phobias; obsessive-compulsive disorder;post-traumatic stress disorder; sleep disorders induced by stress; painperception such as fibromyalgia; mood disorders such as depression,including major depression, single episode depression, recurrentdepression, child abuse induced depression, mood disorders associatedwith premenstrual syndrome, and postpartum depression; dysthemia;bipolar disorders; cyclothymia; chronic fatigue syndrome; stress-inducedheadache; cancer; irritable bowel syndrome, Crohn's disease; spasticcolon; post operative ileus; ulcer; diarrhea; stress-induced fever;human immunodeficiency virus infections; neurodegenerative diseases suchas Alzheimer's disease, Parkinson's disease and Huntington's disease;gastrointestinal diseases; eating disorders such as anorexia and bulimianervosa; hemorrhagic stress; chemical dependencies or addictions,including dependencies or addictions to alcohol, cocaine, heroin,benzodiazapines, or other drugs; drug or alcohol withdrawal symptoms;stress-induced psychotic episodes; euthyroid sick syndrome; syndrome ofinappropriate antidiuretic hormone; obesity; infertility; head trauma;spinal cord trauma; ischemic neuronal damage, including cerebralischemia, for example cerebral hippocampal ischemia; excitotoxicneuronal damage; epilepsy; stroke; immune dysfunctions including stressinduced immune dysfunctions, including porcine stress syndrome, bovineshipping fever, equine paroxysmal fibrillation, confinement dysfunctionin chicken, sheering stress in sheep, and human-animal interactionstress in dogs; muscular spasms; urinary incontinence; senile dementiaof the Alzheimer's type; multiinfarct dementia; amyotrophic lateralsclerosis; hypertension; tachycardia; congestive heart failure;osteoporosis; premature birth; hypoglycemia, and Syndrome X in a mammal,including a human, or bird comprising an amount of a compound of theformula I, II or III, or a pharmaceutically acceptable salt thereof,that is effective in the treatment of such disorder or condition, and apharmaceutically acceptable carrier.

[0131] The invention further includes a method for the treatment of (a)a disorder or condition the treatment of which can be effected orfacilitated by antagonizing CRF, including but not limited to disordersinduced or facilitated by CRF, or (b) a disorder or condition selectedfrom inflammatory disorders such as rheumatoid arthritis andosteoarthritis, pain, asthma, psoriasis and allergies; generalizedanxiety disorder; panic; phobias, including social phobia, agoraphobia,and specific phobias; obsessive-compulsive disorder; post-traumaticstress disorder; sleep disorders induced by stress; pain perception suchas fibromyalgia; mood disorders such as depression, including majordepression, single episode depression, recurrent depression, child abuseinduced depression, mood disorders associated with premenstrualsyndrome, and postpartum depression; dysthemia; bipolar disorders;cyclothymia; chronic fatigue syndrome; stress-induced headache; cancer;irritable bowel syndrome, Crohn's disease; spastic colon; post operativeileus; ulcer; diarrhea; stress-induced fever; human immunodeficiencyvirus infections; neurodegenerative diseases such as Alzheimer'sdisease, Parkinson's disease and Huntington's disease; gastrointestinaldiseases; eating disorders such as anorexia and bulimia nervosa;hemorrhagic stress; chemical dependencies or addictions, includingdependencies or addictions to alcohol, cocaine, heroin, benzodiazapines,or other drugs; drug or alcohol withdrawal symptoms; stress-inducedpsychotic episodes; euthyroid sick syndrome; syndrome of inappropriateantidiuretic hormone; obesity; infertility; head trauma; spinal cordtrauma; ischemic neuronal damage, including cerebral ischemia, forexample cerebral hippocampal ischemia; excitotoxic neuronal damage;epilepsy; stroke; immune dysfunctions including stress induced immunedysfunctions, including porcine stress syndrome, bovine shipping fever,equine paroxysmal fibrillation, confinement dysfunction in chicken,sheering stress in sheep, and human-animal interaction stress in dogs;muscular spasms; urinary incontinence; senile dementia of theAlzheimer's type; multiinfarct dementia; amyotrophic lateral sclerosis;hypertension; tachycardia; congestive heart failure; osteoporosis;premature birth; hypoglycemia, and Syndrome X in a mammal, including ahuman, or bird comprising administering to a subject in need of saidtreatment an amount of a compound of the formula I, II or III or apharmaceutically acceptable salt thereof, that is effective in treatingsuch disorder or condition.

[0132] The present invention also provides a pharmaceutical compositionfor and a method of treating a condition comprising administering acompound of I, II, or III, in an amount effective to treat saidcondition, wherein said condition is selected from the group consistingof: a) abnormal circadian rhythm; b) depression, further wherein asecond compound for treating depression is administered, said secondcompound for treating depression having an onset of action that isdelayed with respect to that of said CRF antagonist; and c) emesis. Theaforementioned method can practiced according to the informationprovided in U.S. Provisional Patent Application No. 60/151,183, filedAug. 27, 1999, which describes treatment of the aforementionedconditions using CRF antagonists in general and which is incorporatedherein by reference in its entirety.

[0133] The compounds of formula I, II, and III, described herein canalso be used to treat forms of heart failure described in U.S. Ser. No.09/248,073, supra, and can be made into pharmaceutical compositionstherefore.

[0134] Examples of more specific forms or manifestations of abnormalcircadian rhythm that can be treated according to the present inventioninclude, but are not limited to, time zone change syndrome resulting,seasonal affective disorder, shift-work sleep disorder, irregularsleep-wake pattern, delayed sleep phase syndrome resulting from saidabnormal circadian rhythm, advanced sleep phase syndrome, or non-24 hoursleep wake disorder resulting from said abnormal circadian rhythm.Moreover, the compound of formula I, II, or III can be combined in themethod or pharmaceutical composition for treatment of abnormal circadianrhythm with a second compound that is useful for treating a sleepdisorder, for example tachykinin antagonists, agonists for GABA brainreceptors, metalonergic compounds, GABA brain receptor agonists, 5HT₂receptor antagonists, and D4 receptor binding compounds. However, othercompounds or substances useful for treating a sleep disorder can becombined with a compound of formula I, II, or III. Such methods andcompositions are described in greater detail in U.S. Provisional PatentApplication No. 60/151,183, supra.

[0135] In another embodiment, said condition is depression, and thesecond compound having delayed action for treating depression isselected from the group consisting of selective serotonin reuptakeinhibitors, tricyclic antidepressants, norepinephrine uptake inhibitors,lithium, bupropion, sertraline, fluoxetine, trazodone, and a tricyclicantidepressant selected from the group consisting of imipramine,amitriptyline, trimipramine, doxepin, desipramine, nortriptyline,protriptyline, amoxapine, clomipramine, maprotiline, and carbamazepine,and pharmaceutically acceptable salts and esters of the above-recitedcompounds.

[0136] In another embodiment, the condition being treated is emesis, andthe method further comprises administering a second compound fortreating emesis. The second compound for treating emesis can be selectedfrom, but is not limited to, tachykinin antagonists, 5HT3 antagonists,GABA agonists, and substance P inhibitors. More specific categories ofemesis encompassed in the present invention include emesis induced by acondition or agent selected from the group consisting of pregnancy,vestibular disorder, post-operative sickness, gastrointestinalobstruction, reduced gastrointestinal motility, visceral pain, migraine,change in intercranial pressure, chemotherapy, radiation, toxins, andopioid analgesics.

DETAILED DESCRIPTION OF THE INVENTION

[0137] Methods of preparing the compounds and compositions of thisinvention are described below. In the discussion and reaction schemesthat follow, R₁ through R₉, R₁₁, R₁₂, R₁₆, R₁₇, R₁₉, A, B, G, the dashedlines and structural formulae I, II, III, X, XI, XII and IV, unlessotherwise indicated, are defined as above.

[0138] Whenever reference is made herein to alkyl, both straight andbranched chain alkyl groups are encompassed. For example, “C₁-C₆ alkyl”encompasses both straight and branched chain alkyl groups of one to sixcarbon atoms, including (but not limited to) methyl, ethyl, isopropyl,t-butyl and hexyl.

[0139] Whenever R₂ or R₅ is a heterocyclic group, attachment of thegroup is through a carbon atom.

[0140] Whenever reference is made herein to C₁-C₄ alkyl or C₁-C₆ alkylwhich “may contain one double or triple bond” in the above definitions,it is understood that at least two carbons are present in the alkyl forone double or triple bond.

[0141] Whenever reference is made herein to halo or halogen; fluoro,chloro, bromo or iodio is meant unless indicated otherwise.

[0142] The terms “treatment”, “treating”, and the like, are meant toinclude both slowing or reversing the progression of a disorder, as wellas curing the disorder. These terms also include alleviating or reducingthe symptoms of a disorder or condition, even if the disorder orcondition is not actually eliminated and even if progression of thedisorder or condition is not itself slowed or reversed. The term“treatment” and like terms also include prophylactic treatment ofdisorders and conditions.

[0143] The term “haloalkyl” refers to an alkyl group substituted by oneor more halogen atoms, i.e. one or more fluoro, bromo, iodo, or chloroatoms. Moreover, it is understood that when an alkyl group can be,according to this specification and claims, substituted with, e.g., oneto nine, e.g., nine atoms, that the optional one to nine fluorine atomsare only an option when a sufficient number of carbon atoms is presentin the alkyl group.

[0144] The term “aryl” in the definitions above means, unless otherwiseindicated, an organic radical derived from an aromatic hydrocarbon byremoval of one hydrogen atom. Examples of aryl groups are phenyl andnaphthyl.

[0145] The term “heterocycloalkyl”, unless otherwise specified means a 4to 8 membered mono-carbocyclic ring or bicyclic ring, wherein at leastone carbon atom is replaced with a hetero member selected from oxygen,nitrogen, N-(alkyl), or S(O)_(m), wherein m is zero, 1, 2, or 3.Generally, heterocycloalkyl groups comprise up to four hetero members,preferably 1, 2, or 3 hetero members. Heterocycloalkyl groups of thecompounds of the invention can contain optionally from one to threedouble bonds. The term “heterocycloalkyl” also includes heteroarylgroups. Examples of heteroaryl groups include thienyl, benzothienyl,pyridyl, thiazolyl, quinolyl, pyrazinyl, pyrimidyl, imidazolyl, furanyl,benzofuranyl, benzothiazolyl, isothiazolyl, benzisothiazolyl,benzisoxazolyl, benzimidazolyl, indolyl, and benzoxazolyl. Otherexamples of aryl groups are pyrazolyl, triazolyl, tetrazolyl,isoxazolyl, oxazolyl, pyrrolyl, isoquinolinyl, cinnolinyl, indazolyl,indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, purinyl,oxadiazolyi, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,naphthyridinyl, and furopyridinyl. Preferred heteroaryl groups arethiazolyl, thienyl, benzothienyl, pyridyl, quinolyl, quinazolinyl,quinoxalinyl, pyrazinyl, pyrimidinyl, indazolyl, imidazolyl, furanyl,benzimidazolyl, benzofuranyl, benzothiazolyl, benzisoxazolyl,isothiazolyl, pyrazolyl, pyrrolyl, indolyl, pyrrolopyridyl, oxazolyl,benzoxazolyl, and benzothiadiazolyl. Other preferred heterocycloalkylgroups are tetrahydrofurano, tetrahydropyrano, morpholino, pyrrolidino,piperidino, piperazino, [2,2,1]-azabicyclic rings, [2,2,2]-azabicyclicrings, [3,3,1]azabicyclic rings, quinuclidino, azetidino, azetidinono,oxindolo, dihydroimidazolo, and pyrrolidinono. Heterocyclolalkyl groupsin the compounds of the invention may be C-attached or N-attached wheresuch is possible.

[0146] Compounds of the formula I wherein B is —NR₁R₂, —NHCHR₁R₂,—OCHR₁R₂ or —SCHR₁R₂, and R₃ is methyl, ethyl or chloro (hereinafterR₁₉) may be prepared by reaction of a compound of the formula IV whereinD is Cl, and A, R₄, R₅, and Z are as defined above with reference toformula I, with a compound of the formula BH wherein B is as definedimmediately above. The reaction is carried out in a solvent in thepresence of a base at a temperature of between about 0° to about 230° C.Suitable solvents are organic solvents such as tetrahydrofuran (THF),acetonitrile, dimethylsulfoxide (DMSO), acetone, C₂-C₁₅ alkyl alcohol,chloroform (CHC₁₃), benzene, xylene, toluene, sulfolane, pyridine,quinoline, 2,4,6-trimethylpyridine, acetamide, di-(C₁-C₂)alkylacetamideor 1-methyl-2-pyrrolidinone.

[0147] A preferred method of preparing compounds of the formula Iwherein A is —CR₇ and B is —NR₁R₂ or —NHCHR₁R₂ is the two step proceduredescribed below. First, a compound of the formula IV is reacted with anexcess of R₁NH₂ or NH₃ or an equivalent NH₃ precursor (e.g., NaN₃,nBu₄N⁺N₃— or NH₂OH) at temperature from about 75° C. to about 250° C.and at a pressure from about 0 to about 300 psi, in an appropriatesolvent, as described above, to form a compound of the formula I whereinB is —NHR₁, —NH₂, —NH₂OH or —N₃. Compounds of the formula I wherein B is—N₃ or —NH₂OH can be converted into the corresponding compounds offormula I wherein B is —NH₂ by methods well known in the art such ashydrogenation or reduction. Alkylation of a compound of the formula Iwherein B is —NHR, or —NH₂ with an appropriate alkyl halide in thepresence of an appropriate base such as lithium or sodiumbistrimethylsilylamide, lithium or sodium diisopropylamide,n-butyllithium or potassium t-butoxide, in an appropriate solvent suchas THF, dioxane or methylene chloride, will yield the correspondingcompound of formula I wherein B is —NR₁R₂. Alternatively, reductiveamination of a compound of the formula I wherein B is —NHR, or —NH₂, forexample, acylation, followed by reduction with a borohydride (eg.,sodium borohydride) will form the corresponding compound of formula Iwherein B is —NR₁R₂ or NHCHR₁R₂.

[0148] When B is —NR₁R₂ or —NHCHR₁R₂, an excess of BH may be used bothas a reagent and as a base. Bases other than BH such as potassiumcarbonate, tri-(C₁-C₆)alkylamine or sodium hydride may also be used. Thereaction is carried out at a temperature of about 75° to 230° C. Whenthe reaction is carried out in the presence of a base, such as sodiumhydrilde, potassium C₁-C₄ alkoxide, or an organolithium compound such asn-butyllithium, a molar equivalent of the amine is used.

[0149] When B is —OCHR₁R₂ or —SCHR₁R₂, a base which is capable ofdeprotonating BH may be used, such as an alkali metal hydride such assodium or potassium hydride, or an organometallic base such as sodiumdiisopropylamide, sodium bis(trimethylsilyl)amide, lithiumdiisopropylamide, lithium bis(trimethylsilyl)amide, sodium or potassiumC₁-C₄ alkoxide, or n-butyllithium. The solvent used can be, for example,tetrahydrofuran, acetonitrile, dimethylsulfoxide, acetone, methylenechloride, toluene, a C₂-C₅ alcohol, chloroform, benzene, xylene, or1-methyl-2-pyrrolidinone, and the reaction temperature can range fromabout 0° C. to about 180° C., and is preferably from about 50° C. toabout 80° C.

[0150] Compounds of the formulae I, II and III wherein B is as definedwith reference to formulae I, II and III and R₃ is defined withreference to the same except that R₃ is not methyl or ethyl (hereinafterR₂₀, which is defined as R₃ with the exception that it can not be methylor ethyl) may be prepared by reacting a compound of the formulae I, IIor III wherein R₃ is chloro with a nucleophile of the formula R₂₀H withor without an organic or inorganic base. Suitable bases include sodiumand sodium hydride, when R₂₀H is an alkanol or an alkane thiol; andweaker bases such as potassium carbonate or triethylamine when R₂₀H isan amine. The compounds of formula I wherein R₂₀ is fluoro may beprepared from the corresponding compounds wherein R₂₀ is chloro onreaction with tetrabutylammonium fluoride. Suitable solvents aredimethylsulfoxide, tetrahydrofuran, or methylene chloride, preferablytetrahydrofuran.

[0151] Compounds of the formula I wherein B is —CR₁R₂R₁₁,—C(C═CR₂R₁₂)R₁, —CHR₂OR₁₂, —CHR₂SR₁₂, or —C(O)R₂, and R₃ is R₁₉, asdefined above, may be prepared as depicted in Scheme I.

[0152] Compounds of the formula IV wherein D is cyano and A, R₄, R₅, andR₁₉ are as defined above having formula IVA (not shown), prepared byreacting the corresponding compound wherein D is chloro with potassiumcyanide or copper cyanide in dimethylsulfoxide,1-methyl-2-pyrrolidinone, N,N-dimethylformamide (DMF) or acetamide, arereacted with a Grignard reagent containing group R₂, as defined above,to form the compounds of formula IA. Further reaction of the compound offormula IA with a Grignard reagent containing R₁ as defined aboveprovides the compound of formula IB. Corresponding compounds of formulaIC wherein B′ is —CR₁R₂R₁₁, or —C(C═CR₂R₁₂)R₁ may be prepared byconventional methods. Thus, reaction of IB with an acid, such asconcentrated sulfuric acid in acetic acid, or Burgess inner salt, suchas (carboxysulfamoyl)triethylammonium hydroxide methyl ester, gives acompound of formula IC wherein B′ is —C(═CR₂R₁₂)R₁. Hydrogenation of acompound wherein B′ is —C(═CR₂R₁₂)R₁ using a palladium/carbon (Pd/C) orplatinum dioxide catalyst gives a compound IC wherein B′ is CHR₁R₂.Reaction of compound IB with diethylaminosulfur trifluoride ortriphenylphosphine/carbontetrachloride affords a compound IC wherein B′is —CR₁R₂F or —CR₁R₂Cl, respectively. Reduction of a compound of formulaIA with sodium borohydride gives a compound I wherein B is —CHR₂OH.Alkylation of this —CHR₂OH group with alkyl halide such as alkyl iodidein the presence of a base such as sodium hydride at room temperatureaffords a compound of formula I wherein B is —CHR₂OR₁₂.

[0153] Compounds of the formula II wherein R₃ is R₁₉ as defined abovemay be prepared from compounds of the formula IV wherein R₁₉, R₄, R₅ andA are as defined before, D is chloro, and YR₂₁ is NH or —CHR₂₁ whereinR₂₁ is cyano or —COO(C₁-C₄ alkyl), hereafter formula IVB, as shown inScheme 2.

[0154] Compounds of the formula VII wherein R₄ and R₆ are each hydrogenand Y is N may be prepared by heating compounds of formula IVB with anacid catalyst in a suitable solvent such as toluene, benzene, t-butanol,acetonitrile and acetone, preferably toluene. The acid catalyst may besulfuric acid, hydrochloric acid, p-toluene sulfonic acid, ormethylsulfonic acid, preferably p-toluene sulfonic acid.

[0155] When Y in formula IVB is CH or N, a base may be used todeprotonate the proton of the compound of formula IVB. Suitable solventsare tetrahydrofuran, toluene, and methylene chloride, suitable reactiontemperatures are between about −78° C. and 100° C., preferably −78° to50° C., and suitable bases are sodium hydride, potassium hydride,potassium t-butoxide, lithium bis(trimethylsilyl) amide, and lithium orsodium diisopropylamide.

[0156] Compounds of the formula VlI wherein R₄ and R₆ are each hydrogenmay be deprotonated with a base such as sodium hydride, or anorganometallic compound such as lithium bis(trimethylsilyl)amidefollowed by quenching with an electrophile compound containing the groupR₄, such as R₄L wherein L is a leaving group such as iodo, bromo,mesylate, tosylatie or with p-tolyl-N-fluoro-N-C₁-C₆ alkyl sulfonamide,iodine, p-nitrobenzene, dimethylformamide, di(C₁-C₄ alkyl)ketone,formaldehyde, (C₁-C₄ alkyl) aldehyde or bromine, to provide a compoundof formula VII wherein R₄ is fluoro, chloro, bromo, iodo, hydroxy, C₁-C₄alkyl, S(C₁-C₄ alkyl), CHO, CH(OH)(C₁-C₄ alkyl), C(OH)(di-C₁-C₄ alkyl)or CH₂OH. Further conventional alkylation of the hydroxy group oroxidation of the thioalkyl group leads to compounds of formula VIIwherein R₄ is C₁-C₄ alkoxy and SO_(n)(C₁-C₄ alkyl) wherein n is 1 or 2,respectively. Oxidation of compounds of formula VII wherein R₄ ishydroxy and R₆ is hydrogen affords corresponding compounds wherein CR₄R₆is C═O, which on reductive amination with an appropriate amine convertinto corresponding compounds wherein R₄ is amino. The compounds offormula VII wherein R₄ is nitro or amino may be formed by reactingcompounds of formula VIl wherein R₄ and R₆ are both hydrogen with alkylnitrite to form compounds wherein CR₄R₆ is C═NOH and oxidizing orreducing to give the compounds of formula VII wherein R₄ is nitro oramine, respectively.

[0157] Compounds of the formula VII, when one of R₄ and R₆ is hydrogen,may be converted into corresponding compounds wherein R₁₆ and R₁₇ areboth hydrogen by reduction with a reducing agent such as lithiumaluminum hydride in tetrahydrofuran. The same reduction leads tocompounds wherein R₁₆ is hydrogen and R₁₇ is hydroxy, when both of R₄and R₆ are riot hydrogen. Alkylation when R₁₇ is hydroxy with C₁-C₄alkyl iodide in the presence of sodium hydride gives the correspondingcompound wherein R₁₇ is O(C₁-C₄ alkyl). Reaction of compounds of formulaVII with an organometallic compound such as di(C₁-C₆ alkyl)zinc, C₁-C₆alkyl lithium, or C₁-C₆ alkyl magnesiumbromide affords compounds offormula VII wherein one of R₁₆ or R₁₇ is C₁-C₆ alkyl and the other ishydroxy.

[0158] The conversion of compounds of formula VIII to correspondingcompounds of formula IIA is by the methods described above forpreparation of compounds of formula I.

[0159] The compounds of formula III wherein G is oxygen or sulfur and R₆is hydrogen may be prepared by reacting compounds of formula I whereinR₄ is amino and Z is NH with phosgene, diphosgene, triphosgene orthiophosgene. The reaction is in the presence of a base such astri(C₁-C₄ alkyl)amine in a suitable solvent, preferable tetrahydrofuraneat about −78° to about 50° C., preferably at 0° C. to room temperature.Standard alkylation of these compounds wherein R₆ is hydrogen with asuitable base such as sodium hydride in a suitable solvent such as drytetrahydrofuran provides compounds of the formula III wherein R₆ isC₁-C₄ alkyl.

[0160] Compounds of the formula III wherein G is alkyl may be preparedby reacting a compound of the formula I wherein R₄ is amino and Z is NHwith a compound of the formula GC(OC₁-C₂ alkyl)₃ in the presence of anacid such as p-toluenesulfonic acid (p-TsOH), methanesulfonic acid(MsOH), hydrogen chloride gas (HCl_(g)) or concentrated sulfuric acid(H₂SO₄) in an appropriate sovient such as toluene, xylene, benzene,dioxane or THF at a tempeature from about room temperature to about 140°C., preferably from about 50° C. to about the reflux temperature.Alternatively, a compound of the formula I wherein R₄ is amino and Z isNH can be reacted with [G(C═O)]₂O, G(C═O)Cl or G(C═O)F in the presenceof a base such as pyridine, a derivative of pyridine or atri-(C₁-C₄)alkylamine, in an appropriate solvent such as CH₂Cl₂, CHCl₃,THF, dioxane, toluene or benzene, at a temperature from about 0° C. toabout the reflux temperature of the reaction mixture, preferably fromabout 0° C. to about room temperature, followed by ring cyclizationunder acidic conditions (eg., with pTSOH, MSOH, HCl_(g), hydrogenbromide gas (HBr_(g)) or concentrated H₂SO₄). The ring cyclization canbe carried out in an appropriate solvent such as a C₁-C₅ alcohol,toluene, xylene, benzene, dioxane or THF. Suitable temperatures for thisreaction can range from about room temperature to about 140° C.Preferably, the reaction temperature is between about 50° C. and aboutthe reflux temperature.

[0161] Compounds of the formula III wherein G is —O—(C₋C₂ alkyl) or—OCF₃ may be prepared by reacting a compound of the formula III whereinG is oxygen and R₆ is hydrogen with a compound of the formula GOSO₂CF₃in the presence of a base such as tri(C₁-C₄ alkyl)amine, or with lithiumbistrimethylsilylamide in HMPA or DMF, and then quenching the reactionwith a compound of the formula GOSO₂OG or G—X wherein X is bromo, chloroor SO₃CF₃.

[0162] The compounds of formula IV wherein D is chloro and ZR₅ is NHR₅may be prepared from compounds of formula V:

[0163] wherein A and R₄ are as defined with reference to formula I andR₁₉ is as defined above, by reaction with R₅NH₂. The reaction is intetrahydrofuran or dimethylsulfoxide at about 0° C. to about 150° C.,preferably 50° to 130° C. The compounds of formula IV wherein D ischloro and Z is O, S, CHR₂₁ wherein R₂₁ is an electron deficient groupsuch as cyano, C(═O)R, COOR, wherein R is C₁-C₄ alkyl, benzoyl or allyl,or SO_(n)— phenyl wherein n=0, 1 or 2 may be prepared by reactingcompounds of formula V with R₅OH, R₅SH, R₅NH₂ or R₅CHR₂₁. The reactionproceeds in the presence of a base which is capable of deprotonatingR₅ZH, such as sodium hydride, potassium hydride, potassium carbonate,lithium or sodium bis(trimethylsilyl)amide, lithium or sodiumdialkylamide, sodium or potassium (C₁-C₄ alkoxide) or n-butyllithium,with or without other organometal halides such as copper (I) bromide,iodide or chloride, copper (II) oxide, copper (I) oxide, copper metaland trialkyltinchloride. Examples of solvents that may be used aretetrahydrofuran, dimethylsulfoxide, acetonitrile, methylene chloride,1-methyl-2-pyrrolidinone, pyridine, quinoline, N,N-dialkylacetamides,2,4,6,-trimethylpyridine, N,N-dialkylformamides, e.g.,N,N-dimethylformamide (DMF), hexamethyl phosphoramide and toluene. Thereaction temperature may range from about 0° C. to about 180° C., and ispreferably from about 0° to about 150° C.

[0164] Compounds of the formula IV wherein A is CR₇, D is chloro and Zis O, S, CHR₂₁ may be prepared by reduction of compounds of formula X,depicted below, wherein R₇ and Z are as defined immediately above, witha reducing agent such as phosphorous trichloride in an appropriatesolvent such as methylene chloride or chloroform at temperature fromabout 0° C. to about 100° C., preferably from about room temperature toabout the reflux temperature of the solvent.

[0165] Compounds of the formula X may be prepared from compounds of theformula XI, depicted above, wherein R₄ is as defined as it is forformula I and R₁₉ is as defined above (i.e., methyl or ethyl), byreaction with a compound of the formula R₅OH, R₅SH or R₅CHR₂₁. Thisreactioin proceeds in the presence of a base which is capable ofdeprotonating R₅ZH, such as sodium hydride, potassium hydride, lithium,sodium or potassium bis(trimethylsilyl)amide, lithium, sodium orpotassium dialkylamide, sodium or potassium C₁-C₄alkoxide, orn-butyllithiumri Sui table solvents include tetrahyd rofu ran, dioxane,dimethylsulfoxide, 1-methyl-2-pyrrolidinone, pyridine, N,N-di-(C₁-C₄alkyl)acetamides, acetamide, N,N-di-(C₁-C₄ alkyl)formamides,acetonitrile, methylene chloride, touluene and xylene. Suitable reactiontemperatures may range from about −78° C. to about 150° C., and arepreferably between about −40° C. to about 150° C.

[0166] Compounds of the formula XI may be prepared by reacting thecorresponding compounds of formul a V where in A is —CR₇ and R₄ and R₁₉are defined as ab ove, with an ox idizing agent such asm-chloroperbenzoic acid, peracetic acid or pertrifluoroacetic acid, in asolvent such as methylene chloride, chloroform, acetic acid, DMF,methanol or a mixture of one or more of the foregoing solvents, attemperature from about 0° C. to about 100° C., preferably from aboutroom temperature to about 60° C.

[0167] When R₄ is an electron withdrawing group such as a NO₂,—COO(C₁-C₄ alkyl), —COOH, CN or —CO(C₁-C₄)alkyl, the reaction order forthe coupling reactions that introduce the B arid ZR₅ groups in thesynthesis of compounds of formula I may be reversed. The B group may beintroduced before the ZR₅ coupling step using the methods analogous tothose described above. For example, compounds of the formula I whereinR₄ is an election deficient group may be prepared by reacting a compoundof the formula XII with a compound of the formula HZR₅. Compounds of theformula XII may be prepared by reacting a compound of the formula Vwherein A is CR₇ and R₁₉ and R₄ are defined as above with a compound ofthe formula B″H in the presence of a base.

[0168] Compounds of the formula IV wherein D is chloro and Z is —N(C₁-C₄alkyl) may be prepared by reacting the corresponding compounds wherein Zis NH with a base, at a temperature from about −78° C. to about 100° C.,preferably from about 0° C. to about room temperature, followed byquenching with C₁-C₄ alkyl iodide or bromide. Suitable bases include,for example, sodium hydride, lithium or sodium bis(trimethylsilyl)amide,lithium or sodium dialkylamide, and n-butyllithium. Suitable solventsinclude, for example, tetrahydrofuran, dimethylsulfoxide, toluene,benzene or methylene chloride.

[0169] Compounds of the formula IV wherein D is chloro, hydroxy or OPwherein P is a standard protecting group for hydroxy and Z is —CR₁₃R₁₄may be prepared by alkylation, using an R₁₃ containing alkylating agentsuch as R₁₃l, compounds of the formula IV wherein Z is —CHR₂₁ in thepresence of a base that is capable of deprotonating the proton in the Zgroup, as mentioned above, followed by quenching with an R₁₄ containingalkylating agent such as R₁₄l. Heating compounds of the formula IVwherein D is chloro or hydrogen and Z is —CH(CN) in about 85% phosphoricacid at about the reflux temperature yields the corresponding compoundsof formula IV wherein D is hydroxy and Z is CH₂. Deprotonation of thecompounds of formula IV wherein Z is CH₂ with a base, such as describedabove for deprotonation of R₅ZH, followed by quenching with a suitableelectrophile such as a (C₁-C₆ alkyl)iodide, iodine, bromine,acetylchloride, formaldehyde, acetone, p-tolyl-N-fluoro-N-(C₁-C₆alkyl)sulfonamide, nitrobenzene, C₁-C₆ alkylnitrite, ethylene oxide ordihaloethane yields the corresponding compounds of formula IV wherein Zis —CHR₁₃, —CH(OH), cyclopropyl or —C(NOH). Further alkylation ofcompounds wherein Z is —CHR₁₃, eg., as described immediately above, withan alkylating agent of the formula R₁₄1, produces the correspondingcompounds wherein Z is —C(R₁₃R₁₄).

[0170] Conversion of —C(R₅)NOH or —CH(OH)R₅ to C(O)R₅ may beaccomplished by known methods. Hydrogenation or reduction of compoundswherein Z is —C═NOH provides compounds wherein Z is —CHNH₂. Some of theintermediates may require a protecting or deprotecting procedure tocontrol the reaction selectivity using standard organic chemistry.

[0171] Compounds of the formula V wherein A is N (hereinafter referredto as compounds of the formula VB) or A is CR₇ (i.e., compounds of theformula VA), and R₄ and R₁₉ are defined as they are for formula I, maybe prepared by reacting the corresponding compounds of formulae VIB andVIA, respectively, with 1 equivalent or an excess of POCl₃ at atemperature from about room temperature to about 180° C., preferably atthe reflux temperature, with or without a solvent. Compounds of formulaVIA may be prepared by the methods analogous to those described in theliterature and well known to those skilled in the art. (See Helv.Chimica Acta., 25, p. 1306-1313 (1942)).

[0172] Compounds of formula VIB may be prepared by reacting 1 equivalentof the HCl salt of R₁₉C(═NH)(NH₂), 1 equivalent of R₄CH(COO-(C₁-C₂alkyl))₂, and 2 equivalents of a base such as a sodium alkoxide, eg.,sodium methoxide in a mixture of an alcohol (eg, methanol), and acetoneat a temperature from about 50° C. to about 200° C., preferably at thereflux temperature.

[0173] When compounds of this invention contain one or more chiralcenters, it is understood that the invention includes the racemicmixtures as well as all individual enantiomers and diastereomers of suchcompounds, and mixtures thereof.

[0174] The subject invention also includes isotopically-labeledcompounds, which are identical to those recited in formulas I, II, orIII, but for the fact that one or more atoms are replaced by an atomhaving an atomic mass or mass number different from the atomic mass ormass number usually found in nature. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, andchlorine, such as ³H, ¹¹C, ¹⁴C, ¹⁸F, ¹²³l and ¹²⁵l. Compounds of thepresent invention and pharmaceutically acceptable salts of saidcompounds that contain the aforementioned isotopes and/or other isotopesof other atoms are within the scope of this invention.Isotopically-labeled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³ H, and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of preparation arid detectability.¹¹C and ¹⁸F isotopes are particularly useful in PET (positron emissiointomography), and ¹²⁵l isotopes are particularly useful in SPECT (singlephoton emission computerized tomography), all useful in brain imaging.Further, substitution with heavier isotopes such as deuterium, i.e., ²H,can afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances.Isotopically labeled compounds of formulas I, II, or III of thisinvention can generally be prepared by carrying out the proceduresdisclosed in the Schemes and/or in the Examples below, by substituting areadily available isotopically labeled reagent for a non-isotopicallylabeled reagent.

[0175] The acid addition salts of compounds of the formulae I, II andIII (“the active compounds of this invention) can be prepared in aconventional manner by treating a solution or suspension of thecorresponding free base with one chemical equivalent of apharmaceutically acceptable acid. Conventional concentration orcrystallization techniques can be employed to isolate the salts.Illustrative of suitable acids are acetic, lactic, succinic, maleic,tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, fumaric,sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic,sulfonic acids such as methanesulfonic, benzene sulfonic,p-toluenesulfonic, and related acids.

[0176] The active compounds of this invention may be administered aloneor in combination with pharmaceutically acceptable carriers, in eithersingle or multiple doses. Suitable pharmaceutical carriers include inertsolid diluents or fillers, sterile aqueous solutions and various organicsolvents. The pharmaceutical compositions formed by combining the novelcompounds of formulae I, II and III and their pharmaceuticallyacceptable carriers can then be readily administered in a variety ofdosage forms such as tablets, powders, lozenges, syrups, injectablesolutions and the like. These pharmaceutical compositions can, ifdesired, contain additional ingredients such as flavorings, binders,excipients and the like. Thus, for purposes of oral administration,tablets containing various excipients such as sodium citrate, calciumcarbonate and calcium phosphate may be employed along with variousdisintegrants such as starch, methylcellulose, alginic acid and certaincomplex silicates, together with binding agents such aspolyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often useful for tabletting purposes. Solid compositions of asimilar type may also be employed as fillers in soft and hard filledgelatin capsules. Preferred materials for this include lactose or milksugar and high molecular weight polyethylene glycols. When aqueoussuspensions or elixirs are desired for oral administration, theessential active ingredient therein may be combined with varioussweetening or flavoring agents, coloring matter or dyes and, if desired,emulsifying or suspending agents, together with diluents such as water,ethanol, propylene glycol, glycerin and combinations thereof.

[0177] For parenteral administration, solutions containing an activecompound of this invention or a pharmaceutically acceptable salt thereofin sesame or peanut oil, aqueous propylene glycol, or in sterile aqueoussolution may be employed. Such aqueous solutions should be suitablybuffered if necessary and the liquid diluent first rendered isotonicwith sufficient saline or glucose. These particular aqueous solutionsare especially suitable for intravenous, intramuscular, subcutaneous andintraperitoneal administration. The sterile aqueous media employed areall readily available by standard techniques known to those skilled inthe art.

[0178] The effective dosages for compounds of the formulae I, II or IIIand their salts will depend on the intended route of administration andfactors such as the age and weight of the patient, as generally known toa physician. The dosages will also depend on the particular illness tobe treated. For instance, the daily dosage for stress-induced illnesses,inflammatory disorders, Alzheimer's disease, gastrointestinal diseases,anorexia nervosa, hemorrhagic stress and drug and alcohol withdrawalsymptoms will generally range from about 0.1 to about 50 mg/kg bodyweight of the patient to be treated. The effective dose can bedetermined by those of ordinary skill in the art by reference to textspertaining to treatment of the particular disorder or condition to betreated.

[0179] Methods that may be used to determine the CRF antagonist acivityof the active compounds of this invention and their pharmaceuticallyacceptable salts are described in Endocrinology, 116,1653-1659 (1985)and Peptides, 10, 179-188 (1985). The binding activities for compoundsof formulae I, II and III, expressed as IC₅₀ values, generally rangefrom about 0.5 nanomolar to about 10 micromolar.

[0180] The present invention is illustrated by the following examples.It will be understood, however, that the invention is not limited to thespecific details of these examples. Melting points are uncorrected.Proton nuclear magnetic resonance spectra (¹H NMR) and C¹³ nuclearmagnetic resonance spectra (C¹³ NMR) were measured for solutions indeuterochloroforin (CDCl₃) and peak positions are expressed in parts permillion (ppm) downfield from tetramethylsilane (TMS). The peak shapesare denoted as follows: s, singlet; d, doublet; t, triplet; q, quartet;m, multiplet; b, broad.

[0181] The following abbreviations are used in the Examples: Ph=phenyl;iPr=isopropyl; HRMS=high resolution mass spectrum.

EXAMPLE 1

[0182] The compounds below were prepared by reaction of(2-chloro-6-methyl-3-nitric-pyridin-4-yl)-(alkyl- or dialkyl)-amine withsubstituted phenol by a method analogous to the following: To a mixtureof (2-chloro-6-methyl-3-nitro-pyridin-4-yl)-(alkyl- or dialkyl)-amine (1mmol) and 2,4,6-trimethylphenol (1 mmol) in dry THF was added potassiumtert-butoxide (1 mmol) and the resulting mixture was stirred at roomtemperature until all starting material was consumed. The mixture wasquenched with water and extracted with ethyl acetate. The organic layerwas dried and concentrated to give the title compound after purificationthrough silica gel column chromatography:

2-[2-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-3-nitro-pyridin-4-(S)-ylamino]-butan-1-ol

[0183] 1H NMR(CDCl₃) d 7.69(,1H), 6.289s,1H), 3.65-3.80(m,2H),3.60m,1H), 2.12(s,3H), 2.08(s,6H), 1.8(brs,1H), 1.5-1 .8(m,2H), 1.01(t,3H) ppm.

(1-Methoxymethyl-propyl)-[6-methyl-3-nitro-2-(4-trifluoromethoxy-phenoxy)-pyridin-4-yl]-amine

[0184] yellow solid, mp. 75-76° C., Anal. For C₁₈H₂₀N₃O₅F₃, calc.C52.05; H, 4.85; N, 10.12; found, C, 52.14; H, 5.04; N, 10.13

2-(2-Amino-4,6-dichloro-phenoxy)-6-methyl-3-nitro-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine

[0185] 1H NMR (CDCl₃) d 9.55(d,1H), 7.23(d,1H), 7.00(d,1H), 6.05(s,1H),3.69(m,1H), 3.49(m,2H), 3.38(s,3H), 2.35(s,3H), 1.78(m,1H), 1.65(m,1H),0.99(t,3H) ppm.

3-Methoxy-2-[4-(1-methoxymethyl-propylamino)-6-methyl-3-nitro-pyridin-2-yloxy]-benzaldehyde

[0186] yellow solid, mp. 126.5-130.5° C., Anal. For C₁₉H₂₃N₃O₆, calc.C58.60; H, 5.95; N, 10.79; found, C, 58.45; H, 6.1 1; N, 10.32

[2-(2,6-Dibromo-4-trifluoromethoxy-phenoxy)-6-methyl-3-nitro-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine

[0187] yellow solid, 1H NMR(CDCl₃) d 8.00(d,1H), 7.49(,2H), 6.35(s,1H),3.64(m,1H), 3.53(m,2H), 3.43(s,3H), 2.20(s,3H), 1.6-1.9(m,4H),1.04(t,3H)ppm.

[2-(2-Bromo-4-chloro-6-methoxy-phenoxy)-6-methyl-3-nitro-pyridin4-yl]-(1-methoxymethyl-propyl)-amine

[0188] yellow solid, mp. 111.8-113.6° C., Anal. For C₁₅H₂₁N₃O₅BrCl,calc, C, 45.54; H, 4.46; N, 8.85; found, C, 45.94; H, 4.32; N, 8.68

[2-(2,4-Dichloro-phenoxy)-6-methyl-3-nitro-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine

[0189] 1H NMR (CDCl₃) d 7.83(d,1H), 7.46(d,1H), 7.30(dd,1H),7.15(dd,1H), 6.33(s,1H), 3.65(m,1 H), 3.51 (m,2H), 3.42(s,3H),2.21(s,3H), 1.82(m,1H), 1.66(m,1H), 1.03(t,3H) ppm.

[2-(2-Bromo-6-chloro-4-methoxy-phenoxy)-6-methyl-3-nitro-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine

[0190] 1H NMR(CDCl₃) d 7.88(d,1H), 7.04(d,1H), 6.93(d,1H), 6.27(s,1H),3.79(s,3H), 3.60(m,1H), 3.4-3.5(m,2H), 3.38(s,3H), 2.15(s,3H),1.78(m,1H), 1.64(m,1H), 0.99(t,3H)

(1 -Methoxymethyl-propyl)-[6-methyl-3-nitro-2-(2,4,6-trimethoxy-phenoxy)-pyridin-4-yl]-amine

[0191] mp. 126.8-129.5° C.; Anal. For C₂₀H₂₇N₃O₇ calc. C, 57.00; H,6.46; N, 9.97; found C, 56.94; H, 6.85; N, 9.66.

EXAMPLE 22-Chloro-N-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-acetamide

[0192] To a solution ofN-4-(1-ethyl-propyl)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine(250 mg, 0.763 mmol) in dry THF was added chloroacetyl chloride (86 mg,0.763 mmol) and triethylamine (77 mg, 0.763 mmol) at 0° C. The resultingmixture was warmed to room temperature and stirred for 1 hr. The mixturewas quenched with water and extracted with ethyl acetate. The organiclayer was dried over anhydrous sodium sulfate, filtered, andconcentrated to dryness to give the title compound as a solid. The solidwas purified through silica gel column chromatography to give 280 mg(91%) of tan crystals, mp. 152-154° C.

[0193] 1H NMR(CDCl₃) d 8.07(brs,1H), 6.88(s,2H), 6.16(s,1H), 4.75(m,1H),4.25(s,2H), 3.33(m,1 H), 2.30(s,3H), 2.18(s,3H), 2.08(s,6H),1.4-1.75(m,4H), 0.97(t,6H) ppm.

[0194] The following compounds were prepared by an analogous method tothat in the preceding paragraph:

3-Chloro-N-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-propionamide

[0195] tan solid,mp. 183-185° C. Anal. For C₂₃H₃₂ClN₃O₂ calc, C, 66.09;H, 7.72; N, 10.05; found, C, 66.27; H, 7.87; N, 9.99.

2-Chloro-N-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-propionamide

[0196] mp. 170-172° C., Anal. For C₂₃H₃₂ClN₃O₂ calc. C, 66.09; H, 7.72;N, 10.05; found C, 66.20; H, 7.52; N, 10.09.

EXAMPLE 3N3-Allyl-N4-(1-ethyl-propyl)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine

[0197] To a solution ofN-4-(1-ethyl-propyl)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine(500 mg, 1.52 mmol) in dry THF was added 1M in THF of lithiumbis(trimethylsilyl)amide (1.6 ml, 1.6 mmol) at −78° C. After stirring at−78° C for 10 min, allyl bromide (0.13 ml, 1.52 mmol) was added and theresulting mixture was stirred at that temperature for 20 min, thenwarmed to room temperature overnight. The mixture was quenched withwater and extracted with ethyl acetate. The organic layer was dried overanhydrous sodium sulfate, filtered, and concentrated to dryness to givethe title compound ;as a green-blue oil. The oil was purified throughsilica gel column chromatography using 5% ethyl acetate in hexane aseluent to give a yellow crystal, mp. 86-88° C.

[0198] 1H NMR(CDCl₃) d 6.87(s,2H), 6.0(m,2H), 5.2-5.35(m,2H), 4.8(d,1H),3.54(d,2H), 3.3(m,1 H), 3.05(s,1 H), 2.30(s,3H), 2.14(s,3H), 2.09(s,6H),1.4-1.6(m,4H), 0.96(t,6H) ppm.

[0199] The following compounds were prepared by an analogous method:

[0200] N3-(3-Chloro-propyl)-N4-(1-ethyl-propyl)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine

[0201] 1H NMR(CDCl₃) d 6.85(s,2H), 6.05(s,1H), 4.9(d,1H), 3.8(m,2H),3.3(m,1H), 3.1(m,2H), 2.3(s,3H), 2.159s,3H), 2.04(s,6H), 1.79m,2H),1.5(m,2H), 1.0(m,6H) ppm.

N4-(1-Ethyl-propyl)-6-methyl-N3-propa-1,2-dienyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3,4-diamine

[0202] 1H NMR(CDCl₃) d 8.93(d,1H), 6.86(s,2H), 6.66(m,1H), 6.09(s,1H),5.4-5.6(m,2H), 5.54(d,1H), 3.27(m,1H), 2.27(s,3H), 2.12(s,3H),2.05(s,6H), 1.6(m,4H), 0.94(t,6H) ppm.

EXAMPLE 42-[3-Amino-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-(S)-ylamino]-butan-1-ol

[0203] A mixture of2-[2-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-3-nitro-pyridin-4-(S)-ylamino]-butan-1-ol(120 mg) and Fe (73 mg) in 12 ml of 1:1 of AcOH:H2O was heated at refluxfor 2 hr. The reaction mixture was concentrated to dryness. The residuewas quenched with water, basified to pH 12 and filtered through celite.The filtrate was extracted with chloroform. The organic layer was washedwith brine, dried and concentrated to give the title compound as ayellow solid. The solid was purified through silica gel columnchromatography using 1:1 EtOAc:hexane as eluent to give the titlecompound as a white solid, mp. 161-162° C.

[0204] 1H NMR(CDCl₃) d 7.03(s,2H), 6.15(s,1H), 3.75(m,2H), 3.47(m,1H),2.25(brs,3H), 2.08(s,6H), 1.5-1.8(m,2H), 0.98t,3H) ppm

EXAMPLE 52-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-nicotinicacid methyl ester

[0205] A mixture of4-chloro-6-methyl-2-(4-Chloro-2,6-dimethyl-phenoxy)-nicotinic acidmethyl ester (77 mg, 0.226 mmol) and 1-ethyl-propyl-amine in DMSO washeated at 120° C. for 4 hr. The mixture was quenched with sat. ammoniumchloride, water, brine and extracted with ethyl acetate. The organiclayer was dried and concentrated to give 140 mg of yellow solid.1HNMR(CDCl₃) d 8.10(d,1H), 7.03(s,2H), 6.09(s,1H), 3.88(s,3H),3.35(m,1H), 2.10(s,3H), 2.08(s,6H), 1.5-1.7(m,4H), 0.96(t,6H) ppm.

EXAMPLE 62-(4-Bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-nicotinicacid methyl ester

[0206] A mixture of4-chloro-6-methyl-2-(4-bromo-2,6-dimethyl-phenoxy)-nicotinic acid methylester and 1-ethyl-propyl-amine in DMSO was heated at 120° C.for 16 hr.The mixture was quenched with water, brine and extracted with ethylacetate. The organic layer was dried and concentrated to dryness. Theresidue was purified through silica gel column chromatography usinghexane to 3% ethyl acetate in hexane as eluent to give the titlecompound as a white solid. 1H NMR(CDCl₃) d 8.1(d,1H), 7.18(s,2H),6.08(s,1H), 3.87(s,3H), 3.35(m,1H), 2.10(s,3H), 2.08(s,6H),1.4-1.7(m,4H), 0.96(t,6H) ppm.

EXAMPLE 74-(1-Ethyl-prop-2-ynylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid methyl ester

[0207] A mixture of4-chloro-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic acid methylester and 1-ethyl-propyl-amine in DMSO was heated at 130° C. overnight.The mixture was quenched with water, brine and extracted with ethylacetate. The organic layer was dried and concentrated to dryness. Theresidue was purified through silica gel column chromatography to givethe title compound. 1 H NMR(CDCl₃) d 8.26(d,1H), 6.87(s,2H), 6.26(s,1H),4.11 (m,1H), 3.87(s,3H), 2.324(m,1H), 2.30(s,3H), 2.17s,3H), 2.08(s,6H),1.92(q,2H), 1.16(t,3H) ppm.

EXAMPLE 84-(s)-(1-Hydroxymethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid methyl ester

[0208] A mixture of4-chloro-2-(2,4,6-trimethyl-phenoxy)-6-methyl-nicotinic acid methylester (500 mg, 1.56 mmol) and (S)-2-amino-1-butanol (696 mg, 7.82 mmol)in DMSO was heated in 130° C. oil bath for 24 hr. The mixture cooled tort and quenched with water and extracted with ethyl acetate. The organiclayer was separated, washed with water, dried over anhydrous sodiumsulfate, filtered, and concentrated to dryness to give 610 mg of crudeproduct as an oil. The oil was purified through silica gel columnchromatography using 30% ethyl acetate in hexane as eluent to give thetitle compound. Anal. calc. for C₂₁ H₂₈N₂O₄. ½H₂O: C, 66.1 1; H, 7.66;N, 7.34; found: C, 66.27; H, 7.60; N, 7.21.

EXAMPLE 94-(1-Ethyl-2-hydroxy-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid methyl ester

[0209] A mixture of4-chloro-2-(2,4,6-trimethyl-phenoxy)-6-methyl-nicotinic acid methylester (250 mg, 0.78 mmol) and 3-amino-pentan-2-ol (320 mg, 3.13 mmol) inDMSO was heated in 130° C. oil bath for 24 hr. The mixture cooled to rtand quenched with water and extracted with ethyl acetate. The organiclayer was separated, washed with water, dried over anhydrous sodiumsulfate, filtered, and concentrated to dryness to give 280 mg of crudeproduct as an oil. The oil was purified through silica gel columnchromatography using 20% ethyl acetate in hexane as eluent to give thetitle compound as a yellow solid, mp 116-120° C.

[0210] 1H NMR(CDCl₃) d 8.17(m,1H), 6.87(s,2H), 6.21&6.14(two s, 1H),3.88(s,3H), 3.8-4.0(m,2H), 3.5(m,1H), 3.3(m,1H), 2.30(s,3H), 2.12(s,3H),2.09(s,6H), 1.8(d,IH), 1.5,-1.8(m,2H), 1.26(d,3H), 0.99(t,3H) ppm.

EXAMPLE 102-(4-Bromo-2,6-dimethyl-phenoxy)-4-(S)-(1-hydroxymethyl-propylamino)-6-methyl-nicotinicacid methyl ester

[0211] A mixture of4-chloro-2-(4-bromo-2,6-trimethyl-phenoxy)-6-methyl-nicotinic acidmethyl ester (850 mg) and (S)-2-amino-1-butanol in DMSO was heated in130° C. oil bath for 24 hr. The mixture cooled to rt and quenched withwater and extracted with ethyl acetate. The organic layer was separated,washed with water, dried over anhydrous sodium sulfate, filtered, andconcentrated to dryness to give 764 mg of crude product as an oil. Theoil was purified through silica gel column chromatography to give thetitle compound. 1H NMR (CDCl₃) d 8.15(d,1H), 7.16(s,2H), 6.18(s,1H),3.86(s,3H), 3.72(m,1H), 3.70(m,1H), 3.54(m,1H), 2.10(s,3H), 2.06(s,6H),1.5-1.8(m,2H), 1.00(t,3H) ppm.

EXAMPLE 112-(4-Bromo-2,6-dimethyl-phenoxy)-4-(S)-(1-methoxymethyl-propylamino)-6-methyl-nicotinicacid methyl ester

[0212] A mixture of4-chloro-2-(4-bromo-2,6-trimethyl-phenoxy)-6-methyl-nicotinic acidmethyl ester and 1-methoxymethyl-propylamine in DMSO was heated in 130°C. oil bath for 24 hr. The mixture cooled to rt and quenched with waterand extracted with ethyl acetate. The organic layer was separated,washed with water, dried over anhydrous sodium sulfate, filtered, andconcentrated to dryness to give crude product. The crude compound waspurified through silica gel column chromatography to give the titlecompound.

EXAMPLE 122-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-methyl-nicotinicacid methyl ester

[0213] A mixture of4-chloro-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-nicotinic acidmethyl ester (9.000 g, 26.45 mmol) and (S)-2-amino-1-butanol (12.7 ml)in 1-methyl-2-pyrrolidinone was heated at 130° C. for 2 hr. then at 100°C. overnight. The mixture cooled to rt and poured into ice-water anddiluted with ethyl acetate. The organic layer was separated, washed withwater, dried over anhydrous sodium sulfate, filtered, and concentratedto dryness to give 13.6 g of crude product as a light yellow oil. Theoil was purified through silica gel column chromatography usingchloroform to 2% MeOH in chloroform as eluent to give 6.6839 g (64%) ofthe title compound as a white glass foam. The glass foam was trituratedwith hexane to give a white solid. The solid was recrystallized fromdi-iso-propyl ether to give a white crystals, mp 122.5-124° C. Anal.calc. for C₂₀H₂₅ClN₂O₄: C, 61.14; H, 6.41; N, 7.13; found: C, 60.98; H,6.43; N, 6.95.

EXAMPLE 132-(4-Chloro-2-methoxy-phenoxy)-4-(S)-(1-hydroxymethyl-propylamino)-6-methyl-nicotinicacid methyl ester

[0214] A mixture of4-chloro-2-(4-Chloro-2-methoxy-phenoxy)-6-methyl-nicotinic acid methylester and (S)-2-amino-1-butanol in 1-methyl-2-pyrrolidinone was heatedat 130° C. overnight. The mixture cooled to room temperature and pouredinto ice-water and diluted with ethyl acetate. The organic layer wasseparated, washed with water, dried over anhydrous sodium sulfate,filtered, and concentrated to dryness. The residue was purified throughsilica gel column chromatography to give the title compound as a solidmp. 92.8-93.8° C., Anal. For C₁₉H₂₃N₂O₅Cl calc. C, 57.80; H, 5.87; 7.09;found, C, 57.70; H, 5.89;, 7.02.

EXAMPLE 142-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-hydroxy-propylamino)-6-methyl-nicotinicacid methyl ester

[0215] A mixture of4-chloro-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-nicotinic acidmethyl ester (500 mg, 1.47 mmol) and 3-amino-pentan-2-ol (758 mg, 7.35mmol) in 1-methyl-2-pyrrolidinone was heated in 130° C. oil bath for 24hr. The mixture cooled to rt and quenched with water and extracted withethyl acetate. The organic layer was separated, washed with water, driedover anhydrous sodium sulfate, filtered, and concentrated to dryness togive an oil. The oil was purified through silica gel columnchromatography using 20% ethyl acetate in hexane as eluent to give thetitle compound as a white crystal, mp 133-135° C.

[0216] 1H NMR(CDCl₃) d 8.19(m,1H), 7.00(s,2H), 6.20&6.14(two sets ofs,1H), 3.8-3.9(m,1H), 3.86(s,3H), 3.3&3.5(two sets of m,1H), 2.07(s,3H),2.06(s,6H), 1.75(m,1H), 1.55(m,1H), 1.24(d,3H), 0.96(t,3H)ppm.

EXAMPLE 152-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-methoxy-propylamino)-6-methyl-nicotinicacid methyl ester

[0217] To a solution of2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-hydroxy-propylamino)-6-methyl-nicotinic acid methyl ester (50 mg, 0.123 mmol) in dry THF wasadded NaH and stirred for 20 min. An excess of Mel was added and theresulting mixture was stirred at rt overnight. The mixture cooled to rtand quenched with water and extracted with ethyl acetate. The organiclayer was separated, washed with water, dried over anhydrous sodiumsulfate, filtered, and concentrated to dryness to give an oil. The oilwas purified through silica gel column chromatography using 20% ethylacetate in hexane asan eluent to give the title compound as a clear oil.1H NMR(CDCl₃) d 8.20(d,1H), 7.00(s,2H), 6.14&6.10(two sets of s,1H),3.859s,3H), 3.47(m,1H), 3.39&3.37(two sets of s,3H), 2.08(s,3H),2.06(s,6H), 1.75(m,1H), 1.58(m,1H), 1 .14(t,3H), 0.95(t,3H)ppm.

EXAMPLE 162-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-oxo-propylamino)-6-methyl-nicotinicacid methyl ester

[0218] The title compound was prepared by Dess-Martin oxidation of2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-hydroxy-propylamino)-6-methyl-nicotinicacid methyl ester. A, white solid was obtained after silica gel columnchromatography. 1H NMR(CDCl₃) d 8.6(d,1H), 7.01(s,2H), 5.899s,1H),3.9-4.0(m,1H), 3.90(s,3H), 2.17(s,3H), 2.07(s,3H), 2.05(s,3H), 1.859m,1H), 1.93(m, 1H), 1.00(t,3H) ppm.

EXAMPLE 17 2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-formyl-propylamino)-6-methyl-nicotinic acid methyl ester

[0219] The title compound was prepared by Dess-Martin oxidation of2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-methyl-nicotinicacid methyl ester. The title compound was obtained after columnchromatography. 1H NMR (CDCl₃) 9.54(d,1H), 8.56(d,1H), 7.01(s,2H),5.93(s,1H), 3.92(m,1H), 3.89(s,3H), 2.08(s,3H), 2.05(s,6H), 1.05(t,3H)ppm.

EXAMPLE 182-(4-Chloro-2,6-dimethyl-phenoxy)-4-(S)-(4-ethyl-2-oxo-oxazolidin-3-yl)-6-methyl-nicotinicacid methyl ester

[0220] A mixture of2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-63-methyl-nicotinicacid methyl ester (106 mg, 0.27 mmol) , triphosgene )27 mg, 0.090 mmol),triethylamine (27 mg, 0.27 mmol) in dry THF was stirred at roomtemperature for 2 hr. The mixture was quenched with water and extractedwith ethyl acetate. The organic layer was separated, washed with water,dried over anhydrous sodium sulfate, filtered, arid concentrated todryness to give 13.6 g of crude product as a white glass foam. The foamwas triturated with hexane/diethyl ether to give a white solid, mp.144-145.5° C., Anal. For C₂₁H₂₃ClN₂O₅ calc.: C, 60.22; H, 5.53; N, 6.69;found: C, 60.10, H, 5.79; N, 6.66.

EXAMPLE 19 2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(S)-{1-[(2-hydroxy-ethylamino)-methyl]-propylamino}-6-methyl-nicotinicacid methyl ester

[0221] To a solution of2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-formyl-propylamino)-6-methyl-nicotinicacid methyl ester in dichloroethane was added 2-amino-ethanol, sodiumcyanoborohydride, acetic acid, anhydrous sodium sulfate. The resultingmixture was heated at reflux and cooled to rt. The mixture was quenchedwith water and extracted with chloroform. The organic layer wasseparated, washed with water, dried over anhydrous sodium sulfate,filtered, and concentrated to dryness. After chromatography, the titlecompound was obtained as a white glass foam. 1H NMR(CDCl₃) d 8.3(d,1H),7.0(s,2H), 6.1(s,1H), 3.9(s,3H), 3.64(m,2H), 3.57(m,1H), 2.90(m,2H),2.83(m,2H), 2.5(brs,2H), 2.09(s,3H), 2.06(s,6H), 1.65(m,2H), 0.97(t,3H)ppm.

EXAMPLE 204-[Ethyl-(2-hydroxy-ethyl)-amino]-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid methyl ester

[0222] A mixture of4-chloro-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic acid methylester and 1-ethyl-propyl-amine in 1-methyl-2-pyrrolidinone was heated at130° C. until starting material was consumed. The mixture was quenchedwith water, brine and extracted with ethyl acetate. The organic layerwas dried and concentrated to dryness. The residue was purified throughsilica gel column chromatography to give the title compound. 1HNMR(CDCl₃) d 6.85(s,2H), 6.40(s,1H), 3.88(s,3H), 3.73(t,2H), 3.43(t,2H),3.31(q,2H), 2.27(s,3H), 2.22(s,3H), 2.06(s,6H), 1.15(t,3H) ppm.

EXAMPLE 214-[Ethyl-(2-methanesulfonyloxy-ethyl-amino]-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid methyl ester

[0223] A mixture of4-[ethyl-(2-hydroxy-ethyl)-amino]-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid methyl ester, methanesulfonyl chloride and triethylamine inmethylene chloride was stirred at rt until all starting material wereconsumed. The mixture was quenched with water, brine and extracted withmethylene chloride. The organic layer was dried and concentrated todryness. The residue was purified through silica gel columnchromatography to give the title compound. 1H NMR(CDCl₃) d 6.83(s,2H),6.25(s,1 H), 4.34(t,2H), 3.86(s,3H), 3.6(t,2H), 3.38(t,2H), 3.09s,3H),2.25(s,3H), 2.20(s,3H), 2.04(s,6H), 1.18(t,3H) ppm.

EXAMPLE 224-[(2-Hydroxy-ethyl)-thiophen-2-ylmethyl-amino]-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid methyl ester

[0224] A mixture of4-chloro-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic acid methylester and 2-[(thiophen-2-ylmethyl)-amino]-ethanol in1-methyl-2-pyrrolidinone was heated at 130° C. overnight. The mixturewas quenched with water, brine and extracted with ethyl acetate. Theorganic layer was dried and concentrated to dryness. The residue waspurified through silica gel column chromatography to give the titlecompound. 1H NMR (CDCl₃) d 7.22(m,1H), 6.94m,2H), 6.84(s,2H),6.44(s,1H), 4.52(s,2H), 3.91(s,3H), 3.679t,2H), 3.369t,2H), 2.279s,3H),2.20(s,3H), 2.07(s,6H) ppm.

EXAMPLE 23

[0225] The following compounds were prepared by the method analogous tothat in Example 5, starting with an appropriate4-chloro-6-methyl-2-(substituted-phenoxy)-nicotinic acid alkyl esterwith an appropriate alkyl- or dialkyl-amine.

4-(2,2-Dimethyl-4-phenyl-[1,3]dioxan-5-ylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid methyl ester

[0226] 1H NMR (CDCl₃) d 8.71(d,2H), 7,1-7.4(m,5H), 6.82(s,2H),5.55(s,1H), 5.229s,1H), 4.29(d,1H), 3.97(d,1H), 3.869s,3H), 3.61(d,1H),2.25(s,3H), 2.01(s,6H), 1.91(s,3H), 1.65(s,3H), 1.61(s,3H) ppm.

2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(S)-(1-hydroxymethyl-propylamino)-6-methyl-nicotinicacid ethyl ester

[0227] 1H NMR(CDCl₃) d 8.01(d,1H), 7.02(s,2H), 6.17(s,1H), 4.33(q,2H),3.71(m,1H), 3.66(m,1H), 3.54m,1H), 2.10(s,3H), 2.07(s,6H),1.5-1.8(m,2H), 1.33(t,3H), 1.00(t,3H) ppm.

4-[Ethyl-(2-methoxy-ethyl)-amino]-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid methyl ester

[0228] 1H NMR(CDCl₃) d 6.83(s,2H), 6.19(s,1H), 3.869s,3H),3.35-3.6(m,4H), 3.35(s,3H), 2.26(s,3H), 2.15(s,3H), 2.06(s,6H),1.179t,3H) ppm.

2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(S,R)-&(S,S)-(1-ethyl-2-hydroxy-propylamino)-6-methyl-nicotinicacid methyl ester

[0229] 1H NMR(CDCl₃) d 8.2(d,1H), 7.01(s2H), 6.20(s, 0.2H),6.15(s,0.8H), 3.92(m,1H), 3.87(s,3H), 3.48(m,0.2H), 3.31(m,0.8H),2.08(s,3H), 2.06(s,6H), 1.5-1.8(m,2H), 1.25(d,3H), 0.96(t,3H) ppm.

2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(R)-(1-hydroxymethyl-propylamino)-6-methyl-nicotinicacid methyl ester

[0230] 1H NMR(CDCl₃) 8.12(d,1H), 7.00(s,2H), 6.16(s,1H), 3.85(s,3H),3.6-3.8(m,2H), 3.53(m,IH), 2.08(s,3H), 2.05(s,6H), 1.5-1.8(m,2H),0.98(t,3H)ppm.

4-(2-Hydroxy-1-hydroxymethyl-ethylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid methyl ester

[0231] 1H NMR(CDCl₃) d 8.44(d,1H), 6.84(s,2H), 6.17(s,1H),3.8-4.0(m,4H), 3.85(s,3H), 3.70(m,1H), 2.60(s,3H), 2.27(s,3H),2.11(s,2H), 2.05(s,6H) ppm.

4-(2-Methoxy-1-methoxymethyl-ethylamino)-6-methyl-2-(2,46-trimethyl-phenoxy)-nicotinic acid methyl ester

[0232] 1H NMR(CDCl₃) d 8.38(d,1H), 6.88(s,2H), 6.18(s,1H), 3.88(s,3H),3.78(m,1H), 3.56(m,2H), 3.44(s,6H), 2.31(s,3H), 2.15(s,3H), 2.09(s,6H)ppm.

4-(1-Hydroxymethyl-2-methoxy-ethylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid methyl ester

[0233] 1H NMR(CDCl₃) d 8.44(d,1H), 6.88(s,2H), 6.21(s,1H), 3.89(s,3H),3.80(m,1H), 3.5-3.7(m,2H), 3.45(s,3H), 2.31(s,3H), 2.16(s,3H),2.09(s,6H) ppm.

2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-hydroxy-butylamino)-6-methyl-nicotinicacid methyl ester

[0234] 1H NMR (CDCl₃) d 8.34(d,1H), 7.069s,2H), 6.16(s,1H), 3.91(s,3H),3.70(m,1H), 3.5(m, 1H), 2.13(s,3H), 2.11 (s,6H), 1.5-1.9(m,4H), 1.01(m,6H) ppm.

EXAMPLE 24[2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-pyridin-3-yl]-methanol

[0235] A mixture of4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid methyl ester (130 mg, 0.332 mmol) and an excess of 1M diisobutylaluminum hydride in THF in dry THF was stirred at −78° C. for 10 min,then warmed to rt. The mixture was quenched with methanol and stirred atroom temperature for 20 min, filtered through celite and washed withmethanol and chloroform. The filtrate was concentrated to dryness. Theresidue was purified through silica gel column chromatography to givethe title compound. 1HNMR(CDCl₃) d 7.03(s,2H), 6.11(s,1H), 5.03(d,1H),4.96(s,2H), 3.32(m,1H), 2.14(s,3H), 2.07(s,6H), 1.4-1.7(m,4H),0.96(t,6H) ppm.

[2-(4-Bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-pyridin-3-yl]-methanol

[0236] The title compound was prepared by the method analogous to thatin the preceding paragraph. 1H NMR(CDCl₃) d 7.18(s,2H), 6.11(s,1H),5.05(d,1H), 4.91(d,2H), 3.31(m,1H), 2.14(s,3H), 2.07(s,6H),1.4-1.7(m,4H), 0.96(t,6H) ppm.

EXAMPLE 252-[3-Hydroxymethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-(S)-ylamino]-butan-1-ol

[0237] A mixture of4-(s)-(1-hydroxymethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid methyl ester and 1M lithium aluminum hydride and aluminum chloridein THF in dry THF was heated at reflux. The mixture was cooled andquenched with water, 2N NaOH, then of water and stirred at roomtemperature for 10 min. White solid formed and was filtered throughcelite, washed with THF. The filtrate was concentrate to dryness to givethe title compound as a white solid after column chromatography,

[0238] mp. 135-137° C.; Anal. For C₂₀H₂₈N₂O₃ calc. C, 69.74; H, 8.19; N,8.13; found C, 69.42; H, 8.34; N, 7.95

[0239] The following compounds were prepared by a method analogous tothat in the preceding paragraph, starting with the corresponding esterand reaction thereof with lithium aluminum hydride and aluminumchloride.

[0240]3-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-hydroxymethyl-6-methyl-pyridin-4-ylamino]-pentan-2-ol

[0241] mp. 180-182° C. 1H NMR(CDCl₃) 7.0(s,2H), 6.18&6.15(two sets ofs,1H), 5.land 5.22(m,1H), 4.92(m,2H), 3.80-4.0(m,1H), 3.20-3.5(m,1H),2.11(s,3H), 2.04(s,6H), 1.4-1.8(m,2H), 1.23(m,3H), 0.98(m,3H) ppm.

2-[2-(2,6-Dimethyl-phenoxy)-3-hydroxymethyl-6-methyl-pyridin-4-ylamino]-butan-1-ol

[0242] 1H (CDCl₃) d 7.05(m,3H), 6.20(s,1H), 4.8-5.0(m,2H), 3.74(m,1H),3.66(m,1H), 3.50(m,1H), 2.0-2.29m,9H), 1.55-1.75(m,2H), 0.99(t,3H) ppm.

3-[3-Hydroxymethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-ylamino]-pentan-2-ol

[0243] 1H NMR(CDCl₃) d 6.86(s,2H), 6.17(s, 1H), 4.0(d,1H), 3.9(m,1H),3.3(m,1H), 2.29(s,3H), 2.14(s,3H), 2.13(s,3H), 2.07(s,6H), 1.8(d,1H),1.4-1.8(m,2H), 1.25(d,3H), 0.99(t,3H) ppm.

2-[2- (4-Chloro-2-methoxy-phenoxy )-3-hydroxymethyl-6-methyl-pyridin-4-ylamino]-butan-1-ol

[0244] 1H NMR(CDCl₃) 6.8-7.0(m,3H), 6.2(s,1H), 5.02(d,1H), 4.7(ABq,2H),3.74(m,5H), 3.350-3.5(m,2H), 2.9(brs,2H), 2.18(s,3H), 1.4-1.7(m,2H),1.23(m,3H), 0.95(t,3H) ppm.

EXAMPLE 262-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-hydroxymethyl-6-methyl-pyridin-4-ylamino]-butan-1-ol

[0245] A mixture of4-(s)-(1-hydroxymethyl-propylamino)-6-methyl-2-(4-chloro-2,6-dimethyl-phenoxy)-nicotinicacid methyl ester and 1 M lithium aluminum hydride in THF was stirred atrt: for 2 hr. The mixture was cooled and quenched with water, 2N NaOH,then of water and stirred at room temperature for 10 min. White solidformed and was filtered through celite washed with THF. The filtrate wasconcentrated to dryness to give the title compound as a white solidafter column chromatography, mp 133-135° C., 1H NMR(CDCl₃) 7.00(s,2H),6.17(s,1H), 5.12(d,1H), 4.90(m,2H), 3.4-3.8(m,3H), 2.12(s,3H),2.04(s,6H), 1.4-1.6(m,2H), 0.99(t,3H) ppm.

[0246] The following compounds were prepared by the method analogous tothat in the preceding paragraph, starting with the corresponding methylester with lithium aluminum hydride:

2-{Ethyl-[3-hydroxymethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amino}-ethanol

[0247] 1H NMR(CDCl₃) d 1H NMR(CDCl₃) 6.86(s,2H), 6.53(s,1H), 4.94(s,2H),3.67(m,2H), 3.1-3.3 (m,4H), 2.28(s,3H), 2.20(s,3H), 2.04(s,6H),1.09(t,3H) ppm.

4-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-hydroxymethyl-6-methyl-pyridin-4-ylamino]-hexan-3-ol

[0248] mp. 145-148° C. 1H NMR(CDCl₃) d 1H NMR(CDCl₃) 7.05(s,2H),6.16(s,1H), 5.3(d,1H), 4.94(s,2H), 3.67(m,1H), 3.40 (m,1H), 2.151(s,3H),2.09(s,6H), 1.4-1.8(m,4H), 1.23(m,3H), 1.02(m,6H) ppm.

2-[2-(4-Chloro-2-methoxy-phenoxy)-3-hydroxymethyl-6-methyl-pyridin-4-(S)-ylamino]-butan-1-ol

[0249] 1H NMR (CDCl₃) d 7.8-7.95(m,2H), 5.02(d,1H), 4.74(ABq,2H),3.74(s,3H), 3.72(m,2H), 3.45m,1H), 2.98(brs,1H), 2.18(s,3H),1.4-1.7(m,2H), 0.95(t,3H) ppm.

4-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-hydroxymethyl-6-methyl-pyridin-4-ylamino]-hexan-3-ol

[0250] 1H NMR (CDCl₃) d 7.05(s,2H), 6.16(s,1H), 5.30(d,1H), 4.94(s,2H),3.67(m,1H), 3.4(m,1H), 2.15(s,3H), 2.09(s,6H), 1.5-1.9(m,4H), 1.01(m,6H)ppm.

[2-(2,4-Dimethoxy-phenylamino)-4-(1-methoxymethyl-propoxy)-6-methyl-pyridin-3-yl]-methanol

[0251] 1H NMR(CDCl₃) d 6.90(d,1H), 6.42(s,1H), 6.40(d,1H), 5.91(s,1H),4.42(m,1H), 4.28(s,2H), 3.79(s,3H), 3.76(s,3H), 3.56(m,2H), 3.40(s,3H),2.33(s,3H), 1.5-1 .85(m,2H,), 1.02(t,3H) ppm.

EXAMPLE 272-(4-Chloro-2,6-dimethyl-phenoxy)-4-(S)-(1-hydroxymethyl-propylamino)-6-methyl-nicotinicacid

[0252] A mixture of2-(4-chloro-2,6-dimethyl-phenoxy)-4-(S)-(1-hydroxymethyl-propylamino)-6-methyl-nicotinicacid methyl ester (113 mg) and lithium hydroxide in dioxane/THF/waterwas stirred at room temperature over night. The mixture was quenchedwith ammonium chloride and extracted with chloroform. The organic layerwas dried and concentrated to give 78 mg of the title compound as awhite solid. 1H NMR(CDCl₃) d 10.55(brs,1H), 9.2(d,1H), 7.06(s,2H),6.3(s,1H), 3.5-3.8(m,3H), 2.11(s,3H), 2.09(s,3H), 2.08(s,3H),1.78(m,1H), 1.62(m,1H), 1.00(t,3H) ppm.

4-(1-Ethyl-prop-2-ynylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid

[0253] mp. 131-133° C., 1H NMR(CDCl₃) d 11.29(brs,1H), 9.35(d,1H), 6.91(s,2H), 6.38(s,1H), 4.12(m,1H), 2.88(m,1H), 2.32(s,3H), 2.19(s,3H),2.09(s,6H), 1.96(m,2H), 1.17(t,6H) ppm.

2-(4-Bromo-2,6-dimethyl-phenoxy)-4-(S)-(1-methoxymethyl-propylamino)-6-methyl-nicotinicacid

[0254] 1H NMR (CDCl₃) d 10.5(brs, 1H), 8.6(d,1H), 7.15(d,2H),6.25(s,1H), 3.3-3.6(m,3H), 3.38(s,3H), 2.11 (s,3H), 2.09(s,3H),2.08(s,3H), 1.5-1.85(m,2H), 0.91(t,3H) ppm.

4-(2-Methoxy-1-methoxymethyl-ethylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid

[0255] 1H NMR(CDCl₃) d 9.44(d,1H), 6.92(s,2H), 6.30(s,1H), 3.80(m,1H),3.58(m,2H), 3.44(s,6H), 2.33(s,3H), 2.16(s,3H), 2.10(s,6H) ppm.

EXAMPLE 28

[0256] The following compounds were prepared by reacting thecorresponding[2-(substituted-phenoxy)-3-chloromethyl-6-methyl-pyridin-4-yl]-(alkyl)-aminewith an appropriate amine.

[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-isobutoxymethyl-6-methyl-pyridin-4-yl]-(1-ethyl-propyl)-amine

[0257] 1H NMR(CDCl₃) d 6.94(s,2H), 6.0(s,1H), 5.13(d,1H), 4.7(s,2H),3.2(m,1H), 3.16(d,2H), 2.02(s,3H), 1.96(s,6H), 1.8(m,1H), 1.3-1.6(m,4H),0.82(t,6H), 0.8(d,6H) ppm.

[3-Ethoxymethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-( 1-ethyl-propyl)-amine

[0258] 1H NMR (CDCl₃) d 6.86(s,2H), 6.03(s,1H), 5.30(d,1H), 4.83(s,2H),3.58(q,2H), 3.35(m,1H), 2.29(s,3H), 2.15(s,3H), 2.06(s,6H),1.5-1.78(m,4H), 1.23(t,3H), 0.967(t,6H)ppm.

2-[3-Butoxymethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-ylamino]-butan-1-ol

[0259] 1H NMR(CDCl₃) d 6.85(s,2H), 6.179s,1H), 5.3(d,1H), 4.82(Abq,2H),3.5-3.8(m,2H), 3.5(t,2H), 2.3(s,3H), 2.15(s,3H, 2.02(s,6H),1.75(brs,1H), 1.5-1.8(m,4H), 1.3-1.5(m,2H), 1.02(t,3H), 0.9(t,3H) ppm.

EXAMPLE 291-[4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl)-ethanol

[0260] The title compound was prepared by reacting4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3-carbaldehydewith methyllithium lithium in THF at −78° C. The desired product wasisolated after silica gel column chromatography to give 60.1% of acolorless oil. 1H NMR(CDCl₃) d 6.87(s,2H), 6.06(s,1H), 5.7(q,1H),3.3(m,1H), 2.29(s,3H), 2.12(s,6H), 2.069s,3H), 1.4-1.7(m,4H),1.59(d,3H), 0.8-1.0(m,6H) ppm.

EXAMPLE 30 Acetic acid4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ylmethylester

[0261] The title compound was obtained by acetylation of[2-(2,4,6-trimethyl-phenoxy)-3-hydroxymethyl-6-methyl-pyridin-4-yl]-(1-ethyl-propyl)-amine.

[0262] 1H NMR(CCl₃) d 6.84(s,2H), 6.04(s,1H), 5.35(s,2H), 5.23(d,1H),3.32(m,1H), 2.28(s,3H), 2.12(s,3H), 2.08(s,3H), 2.07(s,6H),1.4-1.7(m,4H), 0.93(t,6H) ppm.

EXAMPLE 312-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-(1-hydroxy-1-methyl-ethyl)-6-methyl-pyridin-4-(S)-ylamino]-butan-1-ol

[0263] The title compound was prepared by reacting2-(4-chloro-2,6-dimethyl-phenoxy)4-(1-hydroxymethyl-propylamino)-6-methyl-nicotinic acid methyl esterwith an excess of 1M methyl magnesium bromide in THF at room temperatureovernight. Standard work-up procedure gave the title compound aftersilica gel chromatography.

[0264] 1H NMR(CDCl₃) d 7.4(brs,1H), 7.01(s,2H), 6.13(s,1H), 3.7(m,1H),3.6(m,1H), 3.45(m,1H), 2.04(s,3H), 2.03(s,3H), 2.02(s,3H),1.5-1.7(m,2H), 0.98(t,3H) ppm.

EXAMPLE 32[2-(4-Chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-amine

[0265] To a solution of[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-chloromethyl-6-methyl-pyridin-4-yl]-(1-ethyl-propyl)-amine(75 mg, 0.196 mmol) in dry THF was added 1.0M BH₃ in THF (0.59 ml, 0.59mmol) and stirred for 2 hr. The mixture was quenched with dilute HCl andstirred for 5 min. The reaction mixture was neutralized with 2N NaOH,water and extracted with ethyl acetate. The organic layer was separated,dried and concentrated to dryness. The residue was purified throughsilca gel column chromatography to give the title compound as acolorless oil.

[0266] 1H NMR(CDCl₃) d 7.03(s,2H), 6.08(s,1H), 3.73(d,1H), 3.3(m,1H),2.15(s,3H), 2.12(s,3H), 2.08(s,6H), 1.4-1.6(m,4H), 0.96(t,6H) ppm.

EXAMPLE 33[2-(2,6-Dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-amine

[0267] To a solution of[2-(4-bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-pyridin-3-yl]-methanol(43 mg, 0.106 mmol) in dry THF was added 1.0M lithium aluminium hydridein diethyl ether (0.25 ml) and aluminum chloride (28 mg). The resultingmixture was stirred at room temperature overnight. The mixture wasquenched with water, 2NaOH, then water. Solid formed and filteredthrough celite, washed with THF, then chloroform. The filtrate wasconcentrated to dryness. The residue was diluted with water and ethylacetate. The organic layer was separated, dried and concentrated to givethe crude material. The title compound was isolated after silca gelchromatography. 1H NMR(CDCl₃) d 6.9-7.1(m,3H), 6.07(s,1H), 3.35(d,1H),3.33(m,1H), 2.14(s,3H), 2.13(s,3H), 2.12(s,6H), 1.5-1.8(m,4H),0.97(t,6H) ppm.

EXAMPLE 34[2-(4-Bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-amine

[0268] The title compound was prepared by the method analogous to thatin Example 145 as a white solid. 1H NMR(CDCl₃) d 7.19(s,2H), 6.09(s,1H),3.36(d,1H), 3.33(m,1H), 2.15(s,3H), 2.12(s,3H), 2.09(s,6H),1.4-1.8(m,4H), 0.97(t,6H) ppm.

EXAMPLE 354-[4-(1-Ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-benzaldehyde

[0269] To a solution of[2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-aminein dry THF was added n-butyllithium at −78° C. After stirring at −78° C.for 10 min, n,N-dimethylformamide was added and the resulting mixturewas stirred at −78° C. for 20 min, the dry-ice bath was removed. Afterstirring for 5 min, the mixture was quenched with diluted HCl, water andadjusted to pH7.5 and extracted with ethyl acetate. The organic layerwas separated, dried, and concentrated to dryness. The residue waspurified through silicca gel chromatography to give the title compound.1H NMR(CDCl₃) d 9.93(s,1H), 7.60(s,2H), 6.10(s,1H), 3.75(d,1H),3.35(m1H), 2.17(s,6H), 2.13(s,3H), 2.12(s,3H), 1.4-1.8(m,4H), 0.97(t,6H)ppm.

EXAMPLE 36{4-[4-(1-Ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-phenyl}-methanol

[0270] A mixture of4-[4-(1-Ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-benzaldehydeand sodium borohydride in methanol was stirred at room temperature.After standard work-up procedure and purification, the title compoundwas obtained as a solid. 1H NMR(CDCl₃) d 7.06(s,2H), 6.08(s,1H),4.64(s,2H), 3.74(d,1H), 3.33(m,lH), 2.14(s,3H)., 2.13(s,3H), 2.11(s,6H)ppm.

EXAMPLE 37(1-Ethyl-propyl)-[2-(4-methoxymethyl-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-amine

[0271] To a solution of{4-[4-(1-Ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-phenyl}-methanolin dry THF was added 60% NaOH in oil and stirred for 5 min. Excess ofMel was added and stirred at room temperature for 2 hr. After standardworked up procedure and purification, the title compound was obtained asa clear golden oil. 1H NMR(CDCl₃) d 7.02(s,2H), 6.06(s,1H), 4.40(s,3H),3.72(d,1H), 3.39(s,3H), 3.36(m,1H), 2.12(s,3H), 2.11(s,3H), 2.10(s,6H),1.4-1.7(m,4H), 0.95(t,6H) ppm.

EXAMPLE 38[2-(4-Ethyl-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-amine

[0272] To a solution of[2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-aminein dry THF was added n-butyllithium at −78° C. After stirring at −78° C.for 10 min, ethyl iodide was added and the resulting mixture was stirredat −78° C. for 30 min, the dry-ice bath was removed. After stirring for5 min, the mixture was quenched with brine and extracted with ethylacetate. The organic layer was separated, dried, and concentrated todryness. The residue was purified through silica gel chromatography togive the title compound. 1H NMR(CDCl₃) d 6.89(s,2H), 6.07(s,1H),3.72(d,1H), 3.34(m,1H), 2.58(q,2H), 2.16(s,3H), 2.12(s,3H), 2.09(s,6H),1.4-1.7(m,4H), 1.25(t,3H), 0.96(t,6H) ppm.

EXAMPLE 39 2-{4-[4-(1-Ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5-d imethyl-phenyl}-propan-2-ol

[0273] To a solution of[2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-aminein dry THF was added n-butyllithium at −78° C. After stirring at −78° C.for 10 min, acetone was added and the resulting mixture was stirred at−78° C. for 30 min. The dry- ice bath was removed. After stirring for 5min, the mixture was quenched with brine and extracted with ethylacetate. The organic layer was separated, dried, and concentrated todryness. The residue was purified through silica gel chromatography togive the title compound.1H NMR(CDCl₃) d 7.17(s,2H), 6.08(s,1H),3.73(d,1H), 3.33(m,1H), 2.19(s,3H), 2.15(s,3H), 2.12(s,6H),1.4-1.7(m,4H), 1.26(s,6H), 0.96(t,6H) ppm.

EXAMPLE 401-{4-[4-(1-Ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-phenyl}-ethanol

[0274] To a solution of[2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-aminein dry THF was added n-butyllithium at −78° C. After stirring at −78° C.for 10 min, acetaldehyde was added and the resulting mixture was stirredat −78° C. for 30 min, the dry-ice bath was removed. After stirring for5 min, the mixture was quenched with brine and extracted with ethylacetate. The organic layer was separated, dried, and concentrated todryness. The residue was purified through silica gel chromatography togive the title compound. 1H NMR(CDCl₃) d 7.06(s,2H), 4.84(m,1H),6.08(s,1H), 3.73(d,1H), 3.35(m,1H), 2.14(s,3H), 2.12(s,3H), 2.11 (s,6H),1.4-1.7(m,4H), 1.51 (d,3H), 0.96(t,6H) ppm.

EXAMPLE 41(1-Ethyl-propyl)-[2-(4-isopropenyl-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-amine

[0275] The title compound was prepared by reacting of2-{4-[4-(1-Ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-phenyl}-propan-2-olwith Burgess Inner salt (Et₃NS(O)₂NCOOMe in benzene at reflux for 30min. 1H NMR(CDCl₃) d 7.17(s,2H), 6.08(s,1H), 5.34(s,1H), 5.02(s,1H),3.72(d,1H), 3.32(m,1H), 2.12 and 2.15 (two sets of s, 12H),1.4-1.6(m,4H), 0.97(t,6H) ppm.

EXAMPLE 42(1-Ethyl-propyl)-[2-(4-isopropyl-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-amine

[0276] The title compound was prepared by hydrogenation of(1-ethyl-propyl)-[2-(4-isopropenyl-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-amineusing 10% Pd/C as catalyst in ethyl acetate at 55 psi until all startingmaterial were consumed. The title compound was obtained as an oil afterpurification. 1H NMR(CDCl₃) d 6.93(s,2H), 6.10(s,1H), 3.73(brs,1H),3.36(m,1H), 2.18(s,3H), 2.14(s,3H), 2.12(s,6H), 1.4-1.8(m,4H),1.27(d,6H), 0.98(t,6H) ppm.

EXAMPLE 43[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethyl-allyl)-amine

[0277] The title compound was prepared as a clear oil by reduction of4-(1-Ethyl-prop-2-ynylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinicacid with lithium aluminum hydride and aluminum chloride. 1H NMR(CDCl₃)d 6.87(s,2H), 6.08(s,1H), 5.7-5.9(m,1H), 5.1-5.3(m,2H), 3.75-4.0(m,2H),2.30(s,3H), 2.16(s,3H), 2.15(s,3H), 2.08(s,6H), 1.70(m,2H), 1.03(t,3H)ppm.

EXAMPLE 44(1-Ethyl-propyl)-[2-(4-fluoro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-amine

[0278] To a solution of[2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-amine in dry THF was added n-butyllithium at−78° C. After stirring at −78° C. for 10 min, (PhSO2)2NF was added andthe resulting mixture was stirred at −78° C. for 30 min, the dry-icebath was removed. After stirring for 5 min, the mixture was quenchedwith brine and extracted with ethyl acetate. The organic layer wasseparated, dried, and concentrated to dryness. The residue was purifiedthrough silica gel chromatography to give the title compound. 1HNMR(CDCl₃) d 6.77(s,1H), 6.73(s,1H), 6.08(s,1H), 3.3(m,1H), 2.12(s,3H),2.09(s,6H), 2.08(s,3H), 1.4-1.8(m,4H), 0.97(t,6H)ppm.

EXAMPLE 452-[2-(2,6-Dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-ylamino]-butan-1-ol

[0279] The title compound was prepared by the method analogous to thatin Example 33.

[0280] 1H NMR(CDCl₃) d 7.05(m,3H), 6.24(s,1H), 3.4-3.8(m,3H),2.24(s,3H), 2.16(s,3H), 2.10(s,6H), 1.5-1.8(m,2H), 0.99(t3H)ppm.

EXAMPLE 462-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-(S)-ylamino]-butan-1-ol

[0281] To a solution of2-(2,4,6-trimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-methyl-nicotinicacid methyl ester in dry THF was added 1.0M lithium aluminium hydride indiethyl ether (0.25 ml) and aluminum chloride. The resulting mixture washeated at reflux for 2 hr. The mixture was quenched with of water,2NaOH, then water and stirred. Solid formed and was filtered throughcelite, then washed with water and ethyl acetate. The organic layer wasseparated, dried, concentrated, and purification to give the titlecompound as a white solid. Anal. For C₂₀H₂₈N₂O₂. ½H₂O calc. C, 70.90; H,8.52; N, 8.01; found C, 71.18; H, 8.66; N, 8.30

[0282] The following compounds were prepared by the method analogous tothat in the preceding paragraph, using the corresponding 2-(substitutedphenoxy)-4-(alkyl-amino)-6-methyl-nicotinic acid methyl ester withlithium aluminum hydride and aluminum chloride.

3-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-ylamino]-pentan-2-ol

[0283] 1H NMR(CDCl₃) d 6.86(s,2H), 6.17&6.13(two sets of s, 1H),5.0-5.2(m,1 H), 4.9(s,2H), 3.9-4.1(m,1H), 3.5(m,1H), 3.3(m,1H),2.29(s,3H), 2.14(s,3H), 2.08(s,6H), 1.4-1.8(m,2H), 1.27(m,3H),0.98(m,3H) ppm.

3-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yiamino]-pentan-2-ol

[0284] 1H NMR(CDCl₃) d 7.01(s,2H), 6.14&6.11(two sets of s,1H),4.04&3.82(two sets of d,1H), 3.92(m,1H), 3.4&3.2(m,1H), 2.13(s,3H),2.11(s,3H), 2.05(s,6H), 1.4-1.8(m,2H), 1.25(two sets of d, 3H),0.98&0.96(two sets of t,3H) ppm.

EXAMPLE 47Benzyl-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-amine

[0285] A mixture of4-bromo-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine (250 mg, 0.78mmol), benzylethylamine (127 mg, 0.937 mmol), Pd(OAc)2(3.6 mg, 0.0156mmol), (S)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (9.7 mg,0.0156 mmol), potassium t-butoxide (105 mg, 0.781 mmol) in 25 ml oftoluene was heated at reflux for 2 hr. The mixture was cooled to rt,quenched with water and extracted with ethyl acetate. The organic layerwas separated, dried (Na₂SO₄), filtered, and concentrated to give abrown oil. The crude material was purified through silica gel columnchromatography to give the title compound. 1H NMR(CDCl₃) d7.2-7.4(m,5H), 6.86(s,2H), 6.41(s,1H), 4.23(s,2H), 3.07(q,2H),2.31(s,3H), 2.29(s,3H), 2.16(s,3H), 2.06(s,6H), 1.05(t,3H) ppm.

[0286] The following compounds were prepared by the method analogous tothat in the preceding paragraph, using an appropriate4-bromo-2-(substituted phenoxy)-3-methyl-6-alkyl or alkoxy-pyridine withan appropriate amine.

[2-(4-Chloro-2 ,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine

[0287] 1H NMR(CDCl₃) d 7.06(s,2H), 6.13(s,1H), 4.14(d,1H),3.3-3.6(m,3H), 3.42(s,3H), 2.16(s,3H), 2.14(s,3H), 2.09(s,6H),1.5-1.8(m,2H0, 1.03(t,3H) ppm.

2-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-ylamino]-3-phenyl-propan-1-ol

[0288] 1H NMR(CDCl₃) d 8.6(d,1H), 7.2-7.4(m5H), 6.84(s,2H), 6.169s,1H),4.099d,1H), 3.82(m,1H), 3.5-3.7(m,2H), 2.95(d,2H), 2.96(s,3H),2.27(s,3H), 2.14(s,3H), 2.05(s,6H) ppm.

[2-(4-Chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine

[0289] 1H NMR(CDCl₃) d 7.06(s,2H), 6.13(s,1H), 4.2(m,1H), 3.53(m,2H),3.42(s,3H), 2.19(s,3H), 2.14(s,3H), 2.10(s,6H), 1.5-1.8(m,2H),1.03(t,3H) ppm.

[2-(4-Chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethoxymethyl-propyl)-amine

[0290] 1H NMR(CDCl₃) d 7.06(s,2H), 6.14(s,1H), 4.24(d,1H),4.4-4.65(m,5H), 2.19(s,3H), 2.14(s,3H), 2.10(s,6H), 1.8(m,1H),1.65(m,1H), 1.25(t,3H), 1.03(t,3H) ppm.

[3,6-Dimethyl-2-(2,4,6-trimethoxy-phenoxy)-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine

[0291] 1H NMR(CDCl₃) d 6.20(s,2H), 6.08(s,1H), 3.80(s,3H), 3.73(s,6H),3.8(m,2H), 3.39(m,1H), 3.36(s,3H), 2.23(brs,3H), 2.10(s,3H), 1.74(m,1H),1.59(m,1H), 0.969t,3H) ppm.

[2-(4-Bromo-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-(1-ethy-propyl)-amine

[0292] 1H NMR(CDCl₃) d 7.18(s,2H), 6.09(s,1H), 4.43(d,1H), 3.89(s,3H),3,25(m,1H), 2.10(s,9H), 1.4-1.8(m,4H), 0.95(t,6H) ppm.

(1-Ethyl-propyl)-[3-methoxy-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amine

[0293] 1H NMR(CDCl₃) d6.85(s,2H), 6.07(s,1H), 4.44(m,1H), 3.89(s,3H),3.23(m,1H), 2.27(s,3H), 2.09(s,6H), 2.08(s,3H), 1.65(m,2H), 1.45(m,2H),0.93(m,6H) ppm.

[2-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-3-propyl-pyridin-4-yl]-(1-ethyl-propyl)-amine

[0294][2-(4-Bromo-2,6-dimethyl-phenoxy)-6-methyl-3-propyl-pyridin-4-yl]-(1-ethyl-propyl)-amine

[0295] 1H NMR(CDCl₃) d 7.03(s,2H), 6.13(s,1H), 3.8(m,1H), 3.74(s,2H),3.38(m,1H), 2.15(s,3H), 2.05(s,6H), 1.50-1.7(m,4H), 0.97(t,6H) ppm.

(1-Ethyl-propyl)-[6-methyl-3-propyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amine[2-(2,4-Dichloro-6-methyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-(1-ethyl-propyl)-amine

[0296] 1H NMR(CDCl₃) 7.24(d,1H), 7.1(d,1H), 6.1(s,1H), 4.47(d,1H),3.9(s,3H), 3.22(m,1H), 2.12(s,3H), 2.08(s,3H), 1.4-1.7(m,4H), 0.9(t,6H)ppm.

[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-(1-ethyl-propyl)-amine

[0297] 1H NMR(CDCl₃) 7.02(s,2H), 6.07(s,1H), 4.44(brs,1H),3.8-3.95(m,3H), 3.23(m,1H), 2.09(s,6H), 2.08(s,3H), 1.4-1.7(m,4H),0.93(t,6H)ppm.

[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yI]-(1-methoxymethyl-propyl)-amine

[0298] 1H NMR(CDCl₃) d 7.02(s,2H), 6.11(s,1H), 4.71(d,1H), 3.88(s,3H),3.45(m,2H), 3.37(s,3H), 2.10(s,3H), 2.09(s,6H), 1.73(m,1H), 1.59(m,1H),0.98(m,3H) ppm.

[2-(2,4-Dichloro-6-methyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine

[0299] 1H NMR (CDCl₃) d 7.1-7.25(m,2H), 6.13(s,1H), 4.74(d,1H),3.91(s,3H), 3.47(m,1H), 3.39(m,2H), 3.37(s,3H), 2.14(s,3H), 2.10(s,3H),1.78(m,1H), 1.59(m, 1H), 0.98(t,3H)ppm.

[2-(4-Chloro-2-methoxy-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine

[0300] 1H NMR (CDCl₃) d 6.8-7.0(m,3H), 6.17(s,1H), 4.76(d,1H),3.82(s,3H), 3.75(s,3H), 3.3-3.5(m,3H), 3.35(s,3H), 2.19(s,3H),1.73(m,1H), 1.56(m,1H), 0.96(t,3H) ppm.

[2-(3-Chloro-2,6-dimethoxy-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine

[0301] 1H NMR(CDCl₃) d 7.12(d,1H), 6.64(d,1H), 6.12(s,1H)<4.73(d,1H),3.88(s,3H). 3.78(s,3H), 3.70(s,3H), 3.3-3.5(m,3H), 3.35(s,3H),2.11(s,3H), 1.5-1.8(m,2H), 0.96(t,3H) ppm.

(1-Methoxymethyl-propyl)-[3-methoxy-6-methyl-2-(2,4,6-trimethoxy-phenoxy)-pyridin-4-yl]-amine

[0302] 1H NMR(CDCl₃) d 6.19(s,2H), 6.10s,1H), 4.75(m,1H), 3.87(s,3H),3.80(s,3H), 3.73(s,6H), 3.3-3.5(m,2H), 3.35(s,3H), 2.17(s,3H),1.78(m,1H), 1.5(m,1H), 0.96(t,3H) ppm.

[3-Methoxy-2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-yl]-(1-ethoxymethyl-propyl)-amine

[0303] 1H NMR(CDCl₃) d 6.59(s,2H), 6.10(s,1H), 4.70(d,1H), 3.89s,3H),3.77(s,3H), 3.48(m,1H), 3.39(m,2H), 3.37(s,3H), 2.11 (s,3H), 2.10(s,6H),1.74(m,1H), 1.57(m,1H), 0.98(t,3H) ppm.

[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-ethoxy-6-methyl-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine

[0304] 1H NMR(CDCl₃) d 7.07(s,2H), 6.16(s,1H), 4.82(d,1H), 4.20(q,2H),3.54(m,1H), 3.43(m,2H), 3.42(s,3H), 2.15(s,3H), 2.13(s,6H),1.5-1.9(m,2H), 1.439t,3H), 1.02(t,3H) ppm.

EXAMPLE 482-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-(S)-ylamino]-butan-1-ol

[0305] To a solution of[1-(tert-butyl-dimethyl-silanyloxymethyl)-propyl]-[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-aminein dry THF was added 1M tetrabutylammonium fluoride in THF at roomtemperature. The mixture was stirred at room temperature for 2 hr,quenched with water, extracted with ethyl acetate. The organic layer wasseparated, dried and concentrated to dryness. The residue was purifiedby Biotage using 15% ethyl acetate in hexane as eluent to give the titlecompound as a white solid. 1H NMR(CDCl₃) d 7.06(s,2H), 6.18(s,1H),4.04(d,1H), 3.74(m,1H), 3.69(m,1H), 3.53(m,1H), 2.18(s,3H), 2.16(s,3H),2.10(s,6H), 1.6-1.8(m,2H), 1.04(t,3H) ppm.

[0306] The following compounds were prepared by the method analogous tothat in the preceding paragraph, starting with the correspondingtert-butyl-dimethyl-silanyloxymethyl derivative with tetrabutylammoniumfluoride.

2-[3-Methoxy-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-(S)-ylamino]-butan-1-ol

[0307] 1H NMR (CDCl₃) d 6.85(s,2H), 6.15(s,1H), 4.57(d,1H), 3.91(s,3H),3.72(m,1H), 3.61(m,1H), 3.41(m,1H), 2.27(s,3H), 2.10(s,3H), 2.07(s,6H),1.5-1.8(m,3H), 0.98(t,3H) ppm.

2-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin4-ylamino]-butan-1ol

[0308] 1H NMR(CDCl₃) d 7.02(s,2H), 6.16(s,1H), 4.60(d,1H), 3.91(s,3H),3.71(m,1H), 3.61(m,1H), 3.40(m,1H), 2.10(s,3H), 2.08(s,6H), 1.8(brs,1H),1.71(m,1H), 1.68(m,1H), 0.99(t,3H) ppm.

4-[4-(1 -Hydroxymethyl-propylamino)-3-methoxy-6-methyl-pyridin-2-yloxy]-3,5-dimethyl-benzonitrile

[0309] 1H NMR(CDCl₃) d 7.35(s,2H), 6.19(s,1H), 4.7(brs,1H), 3.88(s,3H),3.731(m,1H), 3.64(m,1H), 3.43(m,1H), 2.14(m,9H), 1 .8(brs,1 H), 1.71(m,1H), 1.58(m,1H), 0.99(t,3H) ppm.

EXAMPLE 493-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-ylamino]-pentan-2-ol

[0310] The title compound was prepared by Dess Martin oxidation of2-[2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-(S)-ylamino]-butan-1-olmethylene chloride at room temperature, followed by Gringard reactionusing methyl magnesium bromide in THF.1H NMR(CDCl₃) d 7.07(s,2H),6.18(s,1H), 4.3(brs,1H), 4.0(m,1H), 3.32(m,1H), 2.22(s,3H), 2.17(s,3H),2.11(s,6H), 1.6-1.8(m,2H), 1.30(d,3H), 1.01(t,3H)ppm.

EXAMPLE 502-[2-Methyl-6-(2,4,6-trimethyl-phenoxy)-pyridin-4-ylamino]-butan-1-ol

[0311] The title compound was prepared as an oil by heating2-(2,4,6-trimethyl-phenoxy)-4-(S)-(1-hydroxymethyl-propylamino)-6-methyl-nicotinicacid in 160° C. until all starting material were consumed. Anal. ForC₁₉OH₂₆N₂O₂ H₂O calc. C, 68.65; H, 8.49; N, 8.42; found C, 69.04; H,8.14; N, 8.91

EXAMPLE 51(1-Ethyl-prop-2-ynyl)-[2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amine]

[0312] The title compound was prepared by the method analogous to thatin Example 163.

[0313] 1H NMR(CDCl₃) d 6.89(s,2H), 6.12(d,1H), 5.41(d,1H),3.9-4.2(m,2H), 2.37s,3H), 2.30(s,3H), 2.27(m,1H), 1.76(m,2H), 1.05(t,3H)ppm.

EXAMPLE 522-(4-Bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-pyridin-3-ol

[0314] To a solution of[2-(4-bromo-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-(1-ethy-propyl)-aminein methylene chloride was added BBr₃ at 0° C. and stirred for hr. Themixture was quenched with water and extracted with chloroform. Theorganic layer was separated, dried, and concentrated to give the titlecompound. 1H NMR(CDCl₃) d 7.20(s,2H), 6.12(s,1H), 4.77(d,1H),3.27(m,1H), 2.13(s,3H), 2.10(s,6H), 1.4-1.8(m, 4H), 0.97(t,6H) ppm.

[0315] The following compounds were prepared by the method analogous tothat in the preceding paragraph, starting with an appropriate[2-(substituted phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-(alkyl)-aminewith BBr₃ or BBr₃.

4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ol

[0316] 1H NMR(CDCl₃) d6.85(s,2H), 6.10(s,1H), 5.12(brs,1H), 4.21(m,1H),3.27(m,1H), 2.28(s,3H), 2.09(s,9H), 1.5-1.8(m,4H), 0.96(m,6H) ppm.

4-(S)-(1-Hydroxymethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ol

[0317] 1H NMR (CDCl₃) d 6.85(s,2H), 6.17(s,1H), 5.13(brs,1H),4.28(d,1H), 3.73(m,1H), 3.60(m,1H), 3.50(m,1H), 2.27(s,3H), 2.12(s,3H),2.07(s,6H), 1.75(brs,1H), 1.5-1.7(m,2H), 0.99(t,3H) ppm.

2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-methyl-pyridin-3-ol

[0318] 1H NMR(CDCl₃) d 7.032(s,2H), 6.10(s,1H), 5.2(brs,1H),4.35(brs,1H), 3.71(m,1H), 3.61 (m,1H), 3.40(m,1H), 2.07(s,9H), 1.8(brs,1H), 1.71 (m,1H), 1.60(m,1H), 0.99(m,3H) ppm.

2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-pyridin-3-ol

[0319] 1H NMR(CDCl₃) d 7.02(s,2H), 6.10(s,1H), 5.02(brs,1H),4.22(brs,1H), 3.25(brs,1H), 2.08(brs,9H), 1.62(m,2H), 1.52(m,2H),0.95(brs,6H) ppm.

EXAMPLE 53 Chloro-acetic acid4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ylester

[0320] The title compound was prepared by reacting4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-olwith chloroacetyl chloride /triethylamine in THF at 0° C. to rt. 1HNMR(CDCl₃) d 6.84(s,2H), 6.15(s,1H), 4.3(s,2H), 4.0(d,1H), 3.3(m,1H),2.28(s,3H), 2.17(s,3H), 2.08(s,6H), ⅙-1.7(m,4H), 0.9(t,6H) ppm.

EXAMPLE 542-(4-Chloro-2,6-dimethyl-phenoxy)-4-[(1-ethyl-propyl)-methyl-amino]-6-methyl-pyridin-3-ol

[0321] 1H NMR(CDCl₃) d 7.03(s,2H), 6.25(s,1H), 5.4(brs,1H), 3.93(m,1H),2.70(s,3H), 2.12(s,3H), 2.08(s,6H),1.55(m,4H), 0.89(t,6H) ppm.

EXAMPLE 55[4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-acetonitrile

[0322] 1H NMR(CDCl₃) d 6.87(s,2H), 6.13(s,1H), 3.83(d,1H), 3.79(S,2H),3.38(m,1H), 2.30(s,3H), 2.27(s,3H), 2.21 (s,6H), 1.4-1.8(m,4H),1.00(t,6H) ppm.

EXAMPLE 564-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3-carbaldehyde

[0323] 1H NMR(CDCl₃) d 10.52(s,1H), 9.26(d,1H), 6.89(s,2H), 6.11(s,1H),3.42(m,1H), 2.31 (s,3H0, 2.15(s,3H), 2.11 (s,6H), 1.45-1.75(m,4H),0.97(t,6H) ppm.

EXAMPLE 57(1-Ethyl-propyl)-[3-[(1-ethyl-propylimino)-methyl]-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amine

[0324] 1H NMR(CDCl₃) d 10.33(d,1H), 8.94(s,1H), 6.89(s,2H), 6.10(s,1H),3.41(m,1H), 2.86(m,1H), 2.99(s,3H), 2.14(s,3H), 2.10(s,6H),1.4-1.89m,8H), 0.94(t,6H), 0.87(t,6H) ppm.

EXAMPLE 582-[4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ylmethyl]-malonicacid dimethyl ester

[0325] To a solution of dimethylmalonate (60 mg, 0.44 mmol) and 60% NaHin oil (20 mg, 0.44 mmol) in dry THF was added[3-Chloromethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethyl-propyl)-aminehydrogen chloride (50 mg, 0.146 mmol) at room temperature for 1 hr. Themixture was quenched with water and extracted with ethyl acetate. Theorganic layer was separated, dried and concentrated to dryness. Theresidue was purified through silica gel column chromatography to givethe title compound as a clear oil. 1H NMR (CDCl₃) d 6.88(s,2H),6.03(s,1H), 4.85(m,1H), 4.03(t,1H), 3.73(s,6H), 3.26(m,1H), 3.18(d,2H),2.30(s,3H), 2.13s,3H), 2.07(s,6H), 1.5-1.8(m,4H), 0.97(t,6H)ppm.

EXAMPLE 592-[4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ylmethyl]-malonicacid diisopropyl ester

[0326] The title was prepared by the method analogous to that in Example581. 1H NMR (CDCl₃) d 6.87(s,2H), 6.03(s,1H), 5.10(m,2H), 4.90(d,1 H),3.94(t,1H), 3.31(m,1H), 3.16(d,2H), 2.30(s,3H), 2.13s,3H0, 2.08(s,6H),1.5-1.8(m,4H), 1.1-1.3(two sets of d, 6H), 0.97(t,6H)ppm.

EXAMPLE 604-(1-Ethyl-propoxy)-6-methyl-3-nitro-2-(2,4,6-trimethyl-phenoxy)-pyridine

[0327] To a mixture of2-chloro-4-(1-ethyl-propoxy)-6-methyl-3-nitro-pyridine (500 mg, 1.93mmol) and 2,4,6-trimethylphenol (289 mg, 2.13 mmol) in dry THF was addedpotassium t-butoxide. The resulting mixture was stirred at rt.overnight. The mixture was quenched with water, brine and extracted 3times with ethyl acetate. The organic layer was separated, dried (MgSO₄)and concentrated to dryness. After silica gel column chromatographypurification, the title compound was obtained as a light yellow crystal,mp 106-109° C. Anal. For C₂₀H₂₆N₂O₄ calc. C, 67.02; H, 7.31; N, 7.82;found, C, 67.34; H, 7.40; N, 7.42.

EXAMPLE 614-(1-Ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ylamine

[0328] A mixture of4-(1-ethyl-propoxy)-6-methyl-3-nitro-2-(2,4,6-trimethyl-phenoxy)-pyridine(150 mg, 0.418 mmol) and 10% Pd/C (23 mg) in ethanol was hydrogenated at50 psi for 15 hours. An additional 10 Pd/C was added and the resultingmixture was hydrogenated for an additional 24 hr. The mixture wasfiltered through celite and the filtrate was concentrated to dryness togive 200 mg of the crude material. After column chromatography, thetitle compound was prepared as a the corresponding HCl salt as a whitesolid, mp 96-98° C.

EXAMPLE 62[4-(1-Ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-dimethyl-amine

[0329] To a solution of4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ylaminein dry THF was added lithium bis(trimethylsilyl)amide at −78° C. Afterstirring at −78° C. for 10 minutes, an excess of methyl iodide wasadded. The title compound was isolated after quenching with water andextracting with ethyl acetate. The crude material was purified by silicagel column chromatography to give the title compound as a tan foam.

EXAMPLE 63N-[4-(1-Ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-succinamicacid

[0330] A mixture of4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ylamine(100 mg, 0.304 mmol), succinic anhydride 31 mg,0.304 mmol) andtriethylamine in methylene chloride was stirred at rt. overnight. Themixture was quenched with water, and extracted with methylene chloride.The organic layer was separated, dried and concentrated to give a solid.The title compound was isolated as a white crystal after silica gelcolumn chromatography.

[0331] 1H NMR(CDCl₃) d 6.90(brs,1H), 6.84(s,2H), 6.37(s,1H), 4.2(m,1H),2.6-2.8(m,4H), 2.28(s,3H), 2.22(s,3H), 2.03(s,6H), 1.69(m,4H),0.94(t,6H) ppm.

EXAMPLE 644-(1-Ethyl-propoxy)-3,6-dimethyl-2-[3-(2,4,6-trimethyl-pyridinoxy)]-pyridine

[0332] To a solution of 3-pentanol (0.11 ml) in dry THF was added sodiumhydride (60% in oil, 20 mg). After stirring for 5 min, a solution of4-chloro-2,5-dimethyl-6-[3-( 2,4,6-trimethyl-pyridinoxy)]-pyridine (92mg, 0.332 mmol) in THF was added. DMSO was added and the resultingmixture was heated at 130° C. oil bath overnight. The mixture wasquenched with water, brine and extracted 3 times with ethyl acetate. Theorganic layer was separated, dried (MgSO₄) and concentrated to dryness.After silica gel column chromatography purification, the title compoundwas obtained as a clear oil. 1H NMR (CDCl₃) d 6.88 (s,1H), 6.37(s,1H),4.21 (m,1H), 2.5(s,3H), 2.29(s,3H), 2.19(s,3H), 2.18(s,3H), 2.07(s,3H),1.70(m,4H), 0.98(t,6H) ppm. The oil was prepared as the correspondingHCl salt to give a white solid (63 mg).

[0333] The title compounds of the following Examples 65 and 66 wereprepared by the methods analogous to that in Example 64, starting withan appropriate 6-alkyl-4-chloro-orbromo-3-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine with 3-pentanol/NaH:

EXAMPLE 656-Ethyl-4-(1-ethyl-propoxy)-3-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine

[0334] 1H NMR(CDCl₃) d 6.87(s,2H), 6.28(s,1H), 4.20(m,1H), 2.46(q,2H),2.30(s,3H) 2.20(s,3H), 2.07(s,6H), 1.72(m,4H), 1.05(t,3H), 0.99(t,6H)ppm.

EXAMPLE 664-(1-Ethyl-propoxy)-2-(4-fluoro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridine

[0335] colorless oil. Anal. For C₂₀H₂₆FNO₂ calc. C, 72.48; H, 7.91; N,4.23; found C, 72.39; H, 7.77; N, 4.10.

EXAMPLE 67[4-(1-Ethyl-propoxy)-3,6-dimethyl-pyridin-2-yl]-(2,4,6-trimethyl-phenyl)-amine

[0336] To a solution of4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinicacid (240 mg, 0.673 mmol) in dry THF was added lithium aluminum hydrideand aluminum chloride. The resulting mixture was heated at reflux for 3hours. The mixture was quenched with 0.1 ml water and 0.1 ml 2N NaOH,then quenched with water and ethyl acetate. The organic layer wasseparated, dried and concentrated to give 250 mg of brown oil. Aftersilica gel column chromatography, 170 mg(78%) of the title compound wasobtained which was prepared as a HCl salt as a white solid, mp. 132-133°C. 1H NMR(CDCl₃) d 6.87(s,2H), 6.09(s,1H), 5.399brs,1H), 4.13(m,1H),2.27(s,3H), 2.22(s,3H), 2.15(s,6H), 1.98(s,3H), 1.67(m,4H), 0.94(t,6H)ppm.

EXAMPLE 68[4-(1-Ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl-methanol

[0337] To a solution of4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinicacid (100 mg, 0.281 mmol) in dry THF was added BH₃.DMS. The resultingmixture was heated at reflux overnight. The mixture was quenched withdilute HCl and stirred for 30 minutes, adjusted pH to 7.5-8.5, thenextracted with ethyl acetate. The organic layer was separated, dried andconcentrated to give 100 mg of brown oil. After silica gel columnchromatography, 91 mg(95%) of the title compound was obtained as a whitefoam. Anal. For C₂₁H₃₀N₂O₂. ½H₂O cal. C, 71.76; H, 8.89; N, 7.97; found:C, 71.97; H, 8.90; N, 7.69.

EXAMPLE 69[4-(1-Ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-oxo-acetonitrile

[0338] The title compound was prepared by reacting[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-methanolwith thionyl chloride in benzene, concentrated to dryness, followed byreacting with diethylaluminum cyanide. After standard workup procedureand silica gel column chromatography, the title compound was obtained asa yellow crystal, mp. 108-110° C.

[0339] 1H NMR(CDCl₃) d 8.57(s,1H), 6.97(s,2H), 6.37(s,1H), 4.46(m,1H),2.35(s,3H), 2.34(s,3H), 2.09(s,6H), 1.6-1.8(m,4H), 0.99(t,6H) ppm.

EXAMPLE 70[4-(1-Ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-imidazol-1-yl-methanone

[0340] To a solution of4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinic;acid (250 mg, 0.701 mmol) in 2 ml of DMF was added carbonyldiimidazole(190 mg, 1.19 mmol) and the resulting mixture was stirred at roomtemperature overnight. After standard workup procedure and silica gelcolumn chromatography, 260 mg(91.2%) of the title compound was obtainedas a golden crystal, mp. 120-122° C., Anal. For C₂₄H₃₀N₄O₂. ¼H₂O calc:C, 70.13; H, 7.48; N, 13.63; Found: C, 70.06; H, 7.69; N, 13.37.

EXAMPLE 712-[4-(1-Ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-propan-2-ol

[0341] The title compound was prepared by reacting[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-imidazol-1-yl-methanonewith an excess MeMgBr in THF at rt. After standard workup procedure andsilica gel column chromatography, the title compound was obtained as atan solid, mp. 81-83° C.; Anal. For C₂₂H₃₀N₂O₂. 1.5 H₂O calc.: C,69.49;H, 9.38; N, 7.04; found: C, 69.49; H, 9.27; N, 6.86

EXAMPLE 722-[4-(1-Ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-ylmethyl]-malonicacid dimethyl ester

[0342] The title compound was prepared by reacting[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-methanolwith thionyl chloride in benzene, concentrated to dryness, followed byreacting with methyl malonate/NaH in DMSO. After standard workupprocedure and silica gel column chromatography, the title compound wasobtained as a solid, mp. 96-98° C.; Anal. For C₂₆H₃₆N₂O₅. ⅓H₂O calc.:C,67.51; H, 7.99; N, 6.04; found: C, 67.48; H, 7.99; N, 6.02.

EXAMPLE 733-[4-(1-Ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-propionicacid

[0343] Hydrolysis of2-[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-ylmethyl]-malonicacid dimethyl ester with phosphoic/water at reflux to give the titlecompound as a white foam. Anal. For C₂₃H₃₂N₂O₃. ¾H₂O calc.: C,69.40; H,8.48; N, 7.04; found: C, 69.17; H, 8.62; N, 6.90.

EXAMPLE 74[3-Aminomethyl-4-(1-ethyl-propoxy)-6-methyl-pyridin-2-yl]-(2,4,6-trimethyl-phenyl)-amine

[0344] The title compound was prepared by reacting[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-methanolwith thionyl chloride in benzene, concentrated to dryness, followed byreacting with NH₃(g) at room temperature. After standard workupprocedure and silica gel column chromatography, the title compound wasobtained as a golden oil (80%), Anal. For C₂₁H₃₁N₃O. calc.: C,73.86; H,9.15; N, 12.3; found: C, 73.50; H, 9.25; N, 11.39.

EXAMPLE 752-Chloro-N-[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-ylmethyl]-acetamide

[0345] The title compound was prepared by acylation of3-aminomethyl-4-(1-ethyl-propoxy)-6-methyl-pyridin-2-yl]-(2,4,6-trimethyl-phenyl)-aminewith chloroacetyl chloride. After standard workup procedure and silicagel column chromatography, the title compound was obtained as anoff-white crystal, mp. 142-144° C.; Anal. For C₂₃H₃₂ClN₃O₂. calc.:C,66.09; H, 7.72; N, 10.05; found: C, 65.81; H, 7.64; N, 9.86.

EXAMPLE 76[3-Dimethylaminomethyl-4-(1-ethyl-propoxy)-6-methyl-pyridin-2-yl]-(2,4,6-trimethyl-phenyl)-aminehydrochloride salt

[0346] The title compound was prepared by reacting[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-methanolwith thionyl chloride in benzene, concentrated to dryness, followed byreacting with dimethylamine at room temperature. After standard work-upprocedure and silica gel column chromatography, the title compound wasobtained as an oil. The corresponding HCl salt was prepared as a whitesolid, mp. 85-88° C.; Anal. For C₂₃H₃₅N₃O.2HCl. 1.5 H₂O calc.: C,58.83;H, 8.588; N, 8.94; found: C, 58.32; H, 8.5327; N, 8.64.

EXAMPLE 77 Dithiocarbonic acid O-ethyl esterS-[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-ylmethyl]ester

[0347] The title compound was prepared by reacting[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-methanolwith thionyl chloride in benzene, concentrated to dryness, followed byreacting with NaSCSOEt at room temperature. After standard work-upprocedure and silica gel column chromatography, the title compound wasobtained as a white solid, mp. 55-57° C.; Anal. For C₂₄H₃₄N₂O₂S₂. calc.:C,64.54; H, 7.67; N, 6.27; found: C, 64.67; H, 7.78; N, 6.26.

EXAMPLE 784-(1-Ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinamide

[0348] The title compound was prepared by reacting4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinicacid with thionyl chloride in benzene, concentrated to dryness, followedby reacting with NH₃(g) at room temperature. After standard work-upprocedure and silica gel column chromatography, the title compound wasobtained as an oil. The corresponding HCl salt was prepared as anoff-white solid, mp 185-187° C.; Anal. For C₂₁H₂₉N₃O₂. calc.: C,70.96;H, 8.22; N, 11.82; found: C, 71.30; H, 8.33; N, 11.78.

EXAMPLE 794-(1-Ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinonitrile

[0349] The title compound was prepared by reacting4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinamidewith triphosgen/triethylamine in THF. mp 105-107° C., 1H NMR(CDCl3) d6.90(s,2H), 6.26(brs,1H), 6.05(s,1H), 4.24(m,1 H), 2.28(s,3H),2.25(s,3H), 2.17(s,6H), 1.72(m,4H), 0.97(t,6H) ppm.

EXAMPLE 804-(1-Ethyl-propoxy)-6,N,N-trimethyl-2-(2,4,6-trimethyl-phenylamino)-nicotinamide

[0350] The title compound was prepared by reacting4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinicacid with thionyl chloride in benzene, concentrated to dryness, followedby reacting with dimethylamine at room temperature. After standardwork-up procedure and silica gel column chromatography, the titlecompound was obtained as an oil. The corresponding HCl salt was preparedas a white solid, mp. 197-200° C.; Anal. For C₂₃H₃₃N₃O₂.H₂O. calc.:C,63.07; H, 8.28; N, 9.59; found: C, 63.24; H, 8.07; N, 9.61.

EXAMPLE 81[4-(1-Ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-acetonitrile

[0351] The title compound was prepared by reacting[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-methanolwith thionyl chloride in benzene, concentrated to dryness, followed byreacting with potassium cyanide in DMSO at room temperature. Afterstandard work-up procedure and silica gel column chromatography, thetitle compound was obtained as a pale orange solid, mp. 112-115° C., 1HNMR(CDCl₃) d 6.9(s,2H), 6.14(s,1H), 5.6(brs,1H), 4.22(m,1H), 3.49(s,2H),2.28(s,3H), 2.22(s,3H), 2.16(s,6H), 1.71(m,4H), 0.95(t,6H) ppm.

EXAMPLE 82[2-(4-Bromo-2,6-dimethyl-phenylamino)-4-(1-ethyl-propoxy)-6-methyl-pyridin-3-yl]-methanol

[0352] To a solution of4-(1-ethyl-propoxy)-6-methyl-2-(4-bromo-2,6-dimethyl-phenylamino)-nicotinicacid (130 mg, 0.309 mmol) in dry THF was added BH₃.DMS. The resultingmixture was heated at reflux overnight. The mixture was quenched withdilute HCl and stirred for 30 min, adjusted pH to 7.5-8.5, thenextracted with ethyl acetate. The organic layer was separated, dried andconcentrated to give 100 mg of brown oil. After silica gel columnchromatography, 110 mg(87.3%) of the title compound was obtained as awhite semi-solid. 1H NMR(CDCl₃) d 7.25(s,2H), 6.85(brs,1H), 4.8(brs,2H),4.18(m,1H), 2.2(s,3H), 2.07(s,6H), 1.7(m,4H), 0.95(t,6H) ppm.

EXAMPLE 83[2-(4-chloro-2,6-dimethyl-phenylamino)-4-(1-ethyl-propoxy)-6-methyl-pyridin-3-yl]-methanol

[0353] To a solution of4-(1-ethyl-propoxy)-6-methyl-2-(4-chloro-2,6-dimethyl-phenylamino)-nicotinicacid in dry THF was added BH₃.DMS. The resulting mixture was heated atreflux overnight. The mixture was quenched with dilute HCI and stirredfor 30 minutes, adjusted pH to 7.5-8.5, then extracted with ethylacetate. The organic layer was separated, dried and concentrated to givea brown oil. After silica gel column chromatography, the title compoundwas obtained as a green oil. 1H NMR(CDCl₃) d 7.02(s,2H), 6.83(brs,1H),4.78(s,2H), 4.14(m,1H), 2.2(s,3H), 2.13(s,6H), 1.66(m,4H), 0.93(9t,6H)ppm.

EXAMPLE 84[2-(2,4-Dichloro-phenylamino)-4-(1-ethyl-propoxy)-6-methyl-pyridin-3-yl]-methanol

[0354] To a solution of4-(1-ethyl-propoxy)-6-methyl-2-(2,4-dichloro-phenylamino)-nicotinic acidin dry THF was added BH₃.DMS. The resulting mixture was heated at refluxovernight. The mixture was quenched with dilute HCI and stirred for 30min, adjusted pH to 7.5-8.5, then extracted with ethyl acetate. Theorganic layer was separated, dried and concentrated to give a goldenoil. After silica gel column chromatography, the title compound wasobtained as a golden oil. 1H NMR(CDCl₃) d 8.44(d,1H), 8.18(s,1H),7.32(d,1H), 7.179d,1H), 6.28(s,1H), 4.82(s,2H), 4.21(m,1H), 2.42(s,3H),1.6-1.8(m,4H), 0.94(t,6H) ppm.

EXAMPLE 85[2-(2,4-Dimethoxy-phenylamino)-4-(1-methoxymethyl-propoxy)-6-methyl-pyridin-3-yl]-methanol

[0355] The title compound was prepared by a method analogous to thatdescribed for Example 84, starting with the corresponding nicotinic acidwith BH₃.DMS. 1H NMR(CDCl₃) d 6.91(d,1H), 6.50(m,2H),5.91(s,1H),4.42(m,1H), 4.281(s,2H), 3.79(s,3H), 3.76(s,3H), 3.56(m,2H), 3.40(s,3H),2.33(s,3H), 1.6-1.8(m,2H), 1.02(t,3H) ppm.

EXAMPLE 86[4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-imidazol-1-yl-methanone

[0356] The title compound was prepared by a method analogous to thatdescribed for Example 70, starting with the corresponding nicotinic acidwith carbonyldiimidazole. 1HNMR(CDCl₃) d 8.1(s,1H), 7.52(s,1H),7.05(s,1H), 6.78(s,2H), 6.17(s,1H), 5.97(d,1H), 3.3(m,1H), 2.23(s,3H),2.18(s,3H), 2.00(s,6H), 1.4-1.7(m,4H), 0.93(t,6H) ppm.

EXAMPLE 871-[4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-ethanone

[0357] The title compound was prepared by reacting[4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-imidazol-1-yl-methanonewith methylmagnesium bromide/ethyl ether in methylene chloride. 1HNMR(CDCl₃) d 9.7(d,IH), 6.88(s,2H), 6.10(s,1H), 3.32(m,1H), 2.73(s,3H),2.31(s,3H), 2.10(s,3H), 2.09(s,6H), 1.5-1.7(m,4H), 0.95(t,6H)ppm.

EXAMPLE 88(1-Ethyl-propyl)-[6-methyl-3-propyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amine

[0358] 1H NMR(CDCl₃) d 6.84(s,2H), 6.04(s,1H), 3.81(d,1H), 3.31(m,1H),2.56(t,2H), 2.27(s,3H), 2.12(s,3H), 2.04(s,6H), 1.4-1.7(6H), 1.02(t,3H),0.93(t,6H) ppm.

EXAMPLE 892-[4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ylmethyl]-2-methyl-malonicacid dimethyl ester

[0359] The title compound was prepared by a method analogous to thatdescribed for Example 72. 1H NMR(CDCl₃) 6.87(s,2H), 6.01(s,1H),5.05(m,1H), 3.70(s,6H), 3.4(s,2H), 3.3(m,1H), 2.27(s,3H), 2.12(s,3H),2.07(s,6H), 1.4-1.7(m,4H), 1.48(s,3H), 0.949t,6H) ppm.

EXAMPLE 90[4-(1-Ethyl-propoxy)-6-methyl-pyridin-2-yl]-(2,4,6-trimethyl-phenyl)-amine

[0360] The title compound was prepared by decarboxylation of thecorresponding nicotinic acid at 160° C. oil bath. mp. 98-100° C.; Anal.For C₂₀H₂8N₂O calc. C, 76.88; H, 9.03; N, 8.97; found: C, 76.97; H,9.21; N, 8.99.

[0361] The following title compounds of Examples 204 and 205 wereprepared by reacting of3-methoxy-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine4-carbaldehydewith alkyl-magnesium bromide in THF:

EXAMPLE 912-Ethyl-1-[3-methoxy-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-butan-1-ol

[0362] 1H NMR(CDCl₃) 6.87(s,2H), 6.72(s,1H), 4.90(t,1H), 4.00(s,3H),2.29(s,3H), 2.19(s,3H), 2.06(s,6H), 1.2-1.6(m,5H), 0.92(t,3H),0.88(t,3H) ppm.

EXAMPLE 921-[3-Methoxy-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-2-methyl-butan-1-ol

[0363] 1H NMR(CDCl₃) 6.88(s,2H), 6.74(s,1H), 5.00(m,1H), 4.00(s,3H),2.29(s,3H)., 2.19(s,3H), 2.06(s,6H), 1.4-1.9(m,3H), 0.992(t,3H),0.989(d,3H) ppm.

EXAMPLE 931-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-propan-1-ol

[0364] To a −78° C. solution of4-bromo-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine in dry THF wasadded nBuLi and stirred at that temperature for 20 minutes. Excesspropionaldehyde was added and stirred for 2 hours at −78° C. The mixturewas quenched with water, extracted with ethyl acetate. The organic layerwas washed with brine, dried and concentrated. After columnchromatography, an off-white solid was obtained, mp. 119- 120° C.1HNMR(CDCl₃) d 6.86(s,3H), 4.90(m,1H), 2.281(s,3H), 2.28(s,3H),2.21(s,3H), 2.02(s,6H), 1.65-1.8(m,2H), 1.00(t,3H) ppm.

EXAMPLE 94 4-(1-Methoxy-propyl)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine

[0365] The title compound was prepared by reaction of1-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-propan-1-olwith sodium hydride, followed by quenching with methyl iodide. 1HNMR(CDCl₃) d 6.87(s,2H), 6.74(s,1H), 4.33(m,1H), 3.25(s,3H), 2.28(s,3H),2.27(s,3H), 2.21(s,3H), 2.03(s,6H), 1.6-1.8(m,2H), 0.94(t,3H) ppm.

EXAMPLE 954-(1-Ethoxy-propyl)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine

[0366] The title compound was prepared by reaction of1-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-propan-1-olwith sodium hydride, followed by quenching with ethyl iodide.

[0367] 1H NMR(CDCl₃) d 6.86(s,2H), 6.77(s,1H), 4.41(m,1H),3.22-3.45(m,2H), 2.28(s,3H), 2.27(s,3H), 2.21(s,3H), 2.03(s,6H),1.6-1.8(m,2H), 1.20(t,3H), 0.95(t,3H) ppm.

EXAMPLE 96 4-(1-Allyloxy-propyl)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine

[0368] The title compound was prepared by reaction of1-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-propan-1-olwith sodium hydride, followed by quenching with allyl bromide.

[0369] 1H NMR(CDCl₃) d 6.87(s,2H), 6.78(s,1H), 5.93(m,IH),5.1-5.3(m,2H), 4.48(m,1H), 3.95(m,1H), 3.76(m,1H), 2.29(s,3H),2.26(s,3H), 2.21(s,3H), 2.03(s,6H), 1.6-1.8(m,2H), 0.96(t,3H) ppm.

EXAMPLE 974-(1-Butoxy-propyl)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine

[0370] The title compound was prepared by reacting of1-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-propan-1-olwith sodium hydride, followed by quenching with butyl iodide.

[0371] 1H NMR(CDCl₃) d 6.86(s,2H), 6.76(s,1H), 4.37(m,1H), 3.35(m,1H),3.25(m,1H), 2.28(s,3H), 2.26(s,3H), 2.20(s,3H), 2.03(s,6H),1.6-1.8(m,2H), 1.5-1.65(m,2H), 1.3-1.5(m,2H), 0.96(t,3H), 0.89(t,3H)ppm.

[0372] The title compounds of the following Examples 98 through 102 wereprepared by a method analogous to that described in Example 93 startingwith an appropriate 4-bromo-2-(substituted-phenoxy)-pyridine derivativewith nBuLi, followed by quenching with an appropriate aldehyde.

EXAMPLE 981-[2-(2,4-Dichloro-6-methyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-2-ethyl-butan-1-ol

[0373] one racemate 1H NMR(CDCl₃) d 7.28(d,1H), 7.14(d,1H), 6.80(s,1H),4.92(d,1H), 4.00(s,3H), 2.21(s,3H), 2.13(s,3H), 1.3-1.65(m,5H),0.93(t,3H), 0.87(t,3H) ppm.

[0374] The other racemate 1H NMR (CDCl₃) d 7.18(s,1H), 7.08(d,1H),6.74(d,1H), 5.17(m,1H), 3.93(s,3H), 2.75(m,1H), 2.1-2.25(m,1H),2.16(s,3H), 2.13(s,3H), 1.6-1.8(m,2H), 1.0-1.3(m,2H), 0.93(t,3H),0.72(t,3H) ppm.

EXAMPLE 991-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-2,2,2-trifluoro-ethanol

[0375] mp. 134-139° C., Anal. For C₁₈H₂₀F₃NO₂ calc.: C, 63.71; H, 5.94;N, 4.13; found: C, 63.59; H, 6.00; N, 4.02.

EXAMPLE 1001-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-2,2,2-trifluoro-ethanol

[0376] 1H NMR(CDCl₃) d 6.979s,2H), 6.19(s,1H), 2.14(s,6H), 2.06(s,6H)ppm.

EXAMPLE 101[2-(4-Chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-pyridin-2-yl-methanol

[0377] 1H NMR(CDCl₃) d 8.61(d,1H), 7.71(m,1H), 7.30(m,1H), 7.10(m,1H),7.03(s,2H),6.70(s,1H), 6.03(s,1H), 2.37(s,3H), 2.16(s,3H), 2.03(s,6H),ppm.

EXAMPLE 1021-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-2-ethyl-butan-1-ol

[0378] 1H NMR(CDCl₃) d 7.05(s,2H), 6.759s,1H), 4.90(t,1H), 3.98(s,3H),2.19(s,3H), 2.06(s,6H), 2.13(d,1H), 1.25-1.65(m,5H), 0.92(t,3H),0.87(t,3H) ppm.

[0379] The title compounds of the following Examples 103 through 106were prepared by oxidation of the corresponding alcohol with Dess Martinreagent in DMSO/methylene chloride or pyridinium chlorochromate inmethylene chloride.

EXAMPLE 1031-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-propan-1-one

[0380] mp. 82-85.5° C., Anal. For C₁₉H₂₅NO₂ calc.: C, 76.74; H, 7.80; N,4.71; Found: C, 76.61; H, 7.94; N, 4.66.

EXAMPLE 1041-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-2,2,2-trifluoro-ethanone

[0381] 1H NMR(CDCl₃) d 7.06(s,2H), 6.99(s,1H), 2.42(s,3H), 2.30(s,3H),2.03(s,6H) ppm.

EXAMPLE 105[2-(4-Chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-pyridin-2-yl-methanone

[0382] 1H NMR(CDCl₃) d 8.72(d,1H), 8.17(d,1H), 7.95(m,1H), 7.52(m,1H),7.05(s,2H),6.75(s,1H), 2.25(s,3H), 2.22(s,3H), 2.07(s,6H) ppm.

EXAMPLE 1061-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-2-ethyl-butan-1-one

[0383] 1H NMR(CDCl₃) d 7.05(s,2H), 6.67(s,1H), 3.98(s,3H), 3.09(m,1H),2.61(s,3H), 2.06(s,6H), 1.76(m,2H), 1.51 (m,2H), 0.92(t,6H) ppm.

EXAMPLE 107 4-(1-Ethoxy-2,2,2-trifluoro-ethyl)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy-pyridine

[0384] The title compound was prepared by reacting the correspondingalcohol with NaH, followed by quenching with ethyl iodide.

[0385] 1H NMR(CDCl₃) d 6.92(s,1H), 6.87(s,2H), 4.92(m,1H), 3.60(m2H),2.349s,3H), 2.29(s,3H), 2.26(s,3H), 2.03(s,6H), 1.26(t,3H) ppm.

[0386] The title compounds of the following Examples 108 through 109were prepared by reacting of the corresponding ketone with alkyl lithiumor alkyl magnesium.

EXAMPLE 1082-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-butan-2-ol

[0387] 1H NMR(CDCl₃) d 6.86(m,3H), 2.48(s,3H), 2.28(s,3H), 2.21(s,3H),2.02(s,6H), 1.8-2.1(m,2H), 1.61(s,3H), 0.84(t,3H) ppm.

EXAMPLE 1093-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-pentan-3-ol

[0388] 1H NMR(CDCl₃) d 6.87(s,1H), 6.86(s,2H), 2.43(s,3H), 2.28(s,3H0,2.21(s,3H), 2.0-2.2(m,2H), 2.02(s,6H), 1.7-1.9(m,2H), 1.69(brs,1H),0.8(t,6H) ppm.

EXAMPLE 1101-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-hydroxy-6-methyl-pyridin-4-yl]-2-ethyl-butan-1-one

[0389] The title compound was prepared by reacting1-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-2-ethyl-butan-1-onewith BBr₃ or BCl₃ in THF or methylene chloride.

[0390] 1H NMR (CDCl₃) d 7.04(s,2H), 7.01(s,1H), 3.26(m,1H), 2.24(s,3H),2.08(s,6H), 1 .80(m,2H), 1 .63(m,2H), 0.91 (t,6H) ppm.

EXAMPLE 1114-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinamide

[0391] To a solution of4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)nicotinicacid in anhydrous methylene chloride was added thionyl chloride. Afterstirring for 1 hr, the reaction mixture was concentrated to dryness. Theresidue was dissolved in dry THF and NH3(g) was bubbled in. The reactionmixture was quenched with water and extracted with ethyl acetate. Theorganic layer was separated, dried and concentrated to give a lightyellow solid. The solid was purified through silica gel columnchromatography using 1% methanol in chloroform as eluent to give thetitle compound as a white solid, mp. 85-88° C. 1H NMR(CDCl₃) d9.69(brs,1H), 8.01(brs,1H), 6.87(s,2H), 6.11(s,1H), 5.48(brs,1H),3.31(m,1H), 2.29(s,3H), 2.10(s,3H), 2.07(s,6H), 1.60(m,4H), 0.95(t,6H)ppm.

[0392] The title compounds of the following Examples 112 through 118were prepared by a method analogous to that described in the precedingparagraph, starting with the corresponding nicotinic acid orpyrimidine-5-carboxylic derivative and quenching with an appropriatenucleophile.

EXAMPLE 1124-(1-Ethyl-propylamino)-6,N-dimethyl-2-(2,4,6-trimethyl-phenoxy)-nicotinamide

[0393] 1H NMR(CDCl₃) d 9.8(brs,1H), 8.21(brs,1H), 6.88(s,2H),6.11(s,1H), 3.31(m,1H), 2.92(d,3H), 2.30(s,3H), 2.10(s,3H), 2.07(s,6H),1.60(m,4H), 0.95(t,6H) ppm.

EXAMPLE 1132-(4-Chloro-2,6-dimethyl-phenoxy)-4-(S)-(1-hydroxymethyl-propylamino)-6-methyl-nicotinamide

[0394] 1H NMR(CDCl₃) d 9.7(d,1H), 7.9(brs,1H), 7.0(s,2H), 6.2(s,1H),5.6(brs,1H), 3.7(m,1H), 3.66(m,1H), 3.54(m,1H), 2.07(s,3H), 2.068(s,3H),2.06(s,3H), 1.7(m,1 H), 1.6(m, 1H), 0.99(t,3H) ppm.

EXAMPLE 1142-(4-Chloro-2,6-dimethyl-phenoxy)-4-(S)-(1-hydroxymethyl-propylamino)-6-methyl-nicotinicacid hydrazide

[0395] 1H NMR(CDCl₃) d 9.15(s,1H), 7.04(s,2H), 6.23(s,1H),3.6-3.8(m,2H), 3.53(m,1H), 2.08(s,6H), 2.05(s,3H), 2.04(s,3H),1.5-1.8(m,2H), 1.01 (t,3H) ppm.

EXAMPLE 1152-(4-Chloro-2,6-dimethyl-phenoxy)-N-ethyl-4-(S)-(1-hydroxymethyl-propylamino)-6-methyl-nicotinamide

[0396] 1H NMR(CDCl₃) d 9.74(d,1H), 8.12(s,1H), 7.05(s,2H), 6.23(s,1H),3.5-3.8(m,3H), 3.43(m,2H), 2.06(s,9H), 1.8(brs,1H), 1.5-1.7(m,2H),1.19(t,3H), 1.00(t,3H) ppm.

EXAMPLE 1162-(4-Chloro-2,6-dimethyl-phenoxy)-4-(S)-(1-hydroxymethyl-propylamino)-6,N-dimethyl-nicotinamide

[0397] 1H NMR(CDCl₃) d 9.80(d,1H), 8.12(s,1H), 7.04(s,2H), 6.22(s,1H),3.5-3.8(m,3H), 2.93(d,3H), 2.06(s,9H), 1.8(brs,1H), 1.5-1.7(m,2H),0.99(t,3H) ppm.

EXAMPLE 1172-(4-Chloro-2,6-dimethyl-phenoxy)-N-cyclopentyl4-(S)-(1-hydroxymethyl-propylamino)-6-methyl-nicotinamide

[0398] 1H NMR(CDCl₃) d 9.69(d,1H), 8.13(d,1H), 7.04(s,2H), 6.22(s,1H),4.35(m,1H), 3.4.-3.8(m,3H), 2.056(s,9H), 1.4-2.0(m, 10H), 0.99(t,3H)ppm.

EXAMPLE 1182-(4-Chloro-2,6-dimethyl-phenoxy)-N-cyclopropylmethyl-4-(S)-(1-hydroxymethyl-propylamino)-6-methyl-nicotinamide

[0399] 1H NMR(CDCl₃) d 9.71(d,1H), 8.24(s,1H), 7.05(s,2H), 6.23(s,1H),3.5-3.8(m,3H), 3.27(t,2H), 2.08(s,6H), 2.07(s,3H), 1.8(brs, IH),1.5-1.75(m,2H), 0.99(t,3H), 0.46(m,2H), 0.21(m,2H) ppm.

[0400] The title compounds of the following Examples 232 through 236were prepared by a method analogous to that described for Example 224.

EXAMPLE 1194-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinamide

[0401] A brown solid, mp. 204-206° C.

EXAMPLE 1204-(1-Ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimidine-5-carboxylicacid amide

[0402] Mp. 174-176° C.; Anal. For C₂₀H₂₈N₄O₂ calc.: C, 67.39; H, 7.92;N, 15.72; found: C, 67.90; H, 8.19; N, 14.66. 1H NMR(CDCl₃) d7.95(s,1H), 6.89(s,2H), 5.58(s,1H), 5.4(m,1H), 2.28(s,3H), 2.25(s,3H),2.15(s,6H), 1.75(m,4H), 0.96(t,6H) ppm.

EXAMPLE 1214-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinonitrile

[0403] 1H NMR(CDCl₃) d 6.85(s,2H), 6.06(s,1H), 4.72(d,1H), 3.36(m,1H),2.28(s,3H), 2.17(s,3H), 2.09(s,6H), 1.5-1.8(m,4H), 0.96(t,6H) ppm.

EXAMPLE 122[4-(1-Ethyl-propoxy)-6-methyl-3-nitro-pyridin-2-yl]-(2,4,6-trimethyl-phenyl)-amine

[0404] The title compound was prepared by heating 2-bromo (orchloro)-4-(1-ethyl-propoxy)-6-methyl-3-nitro-pyridine with2,4,6-trimethylaniline in DMSO at 130° C. The reaction mixture wasquenched with water and extracted with ethyl acetate. The organic layerwas separated, dried and concentrated to give crude material. Thematerial was purified through silica gel column chromatography to givethe title compound as a yellow solid. 1H NMR(CDCl₃) d 8.52(s,1H),6.92(s,2H), 6.12(s,1H), 4.31(m,1H), 2.32(s,3H), 2.24(s,3H), 2.18(s,6H),1.77(m,4H0, 1.01(t,6H) ppm.

EXAMPLE 1234-(1-Ethyl-propoxy)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3-diamine

[0405] The title compound was prepared by hydrogenation of thecorresponding 3-nitro derivative with 10% Pd/C in ethanol at 50 psi. Apale gray solid was obtained in 97% yield, mp. 73-75° C. 1H NMR(CDCl₃) d6.89(s,2H), 6.18(s,1H), 4.22(m,1 H), 3.2(brs,2H), 2.29(s,3H),2.19(s,6H), 1.7(m,4H), 0.97(t,6H) ppm.

EXAMPLE 1242-Chloro-N-[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-yl]-acetamide

[0406] The title compound was prepared by acylation of4-(1-ethyl-propoxy)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3-diaminewith chloroacetyl chloride, NEt₃ in THF at room temperature. A tan solidwas isolated, mp. 79-82° C. Anal. For C₂₂H₃₀ClN₃O₂ calc. C, 65.41; H,7.49; N, 10.40; found: C, 65.56; H, 7.62; N, 10.98.

EXAMPLE 125N-Butyl-N-ethyl-6-methyl-3-nitro-N-(2,4,6-trimethyl-phenyl)-pyridine-2,4-diamine

[0407] A mixture ofbutyl-(2-chloro-6-methyl-3-nitro-pyridin-4-yl)-ethyl-amine (700 mg, 2.58mmol) and 2,4,6-trimethylaniline in DMSO was heated in 140° C. oil bathfor overnight. An additional 0.75 ml of 2,4,6-trimethylaniline was addedand the resulting mixture was heated for an additional 48 hours. Themixture was quenched with water, brine and extracted 3 times with ethylacetate. The organic layer was separated, dried (MgSO₄) and concentratedto dryness. After silica gel column chromatography purification, thetitle compound was obtained as an oil.

EXAMPLE 1264-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinicacid

[0408] The title compound was prepared by heating2-chloro-4-(1-ethyl-propylamino)-6-methyl-nicotinic acid andtrimethylaniline in the presence of potassium carbonate and copper inDMF. The desired product was isolated by silica gel columnchromatography using 5% methanol in chloroform as solvent to give a tansolid, mp. 130-135° C.

EXAMPLE 1274-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinicacid methyl ester

[0409] A mixture of 2-chloro-4-(1-ethyl-propylamino)-6-methyl-nicotinicacid methyl ester, trimethylaniline, potassium carbonate, copper in DMFwas heated at reflux. The mixture was quenched with ammonium chlorideand stirred for 20 min, filtered through celite and washed with ethylacetate. The filtrate was extracted with ethyl acetate. The organiclayer was separated, dried and concentrated to dryness. The residue waspurified through silica gel column chromatography using 2% methanol inchloroform as eluent to give the title compound as a solid.

[0410] 1H NMR(CDCl₃) d 8.9(s,1H), 8.0(d,1H), 6.91(s,2H), 5.79s,1H),3.92(s,3H), 3.37(m,1H), 2.30(s,3H), 2.17(s,3H), 2.10(s,6H),1.5-1.7(m,4H), 0.96(t,6H) ppm.

EXAMPLE 128N4-(1-Ethyl-propyl)-3,6-dimethyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,4-diamine

[0411] The title compound was prepared by reduction of4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-nicotinicacid with 1M of lithium aluminium hydride in diethyl ether and aluminiumtrichloride at reflux. 1H NMR(CDCl₃)6.9(s,2H), 6.0(s,1H), 5.4(brs,1H),3.6(d,1H), 3.3(m,1H), 2.32(s,3H), 2.2(s,3H), 2.15(s,6H), 1.4-1.7(m,4H),1.0(t,6H) ppm.

EXAMPLE 1292-[4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-ylmethyl]-malonicacid dimethyl ester

[0412] Mp. 136-138° C.; Anal. For C₂₆H₃₇N₃O₄. ¾H₂O calc.: C,66.57; H,8.27; N, 8.96D; found: C, 66.67; H, 7.95; N, 8.88.

EXAMPLE 130[2-(4-Bromo-2,6-dimethyl-phenylamino)-4-(1-ethyl-propylamino)-6-methyl-pyridin-3-yl]-methanol

[0413] The title compound was prepared by reduction of the correspondingnicotinic acid derivative with BH₃.DMS in THF at reflux. Standardwork-up procedure gave the title compound as a white foam. 1H NMR(CDCl₃)7.15(s,2H), 6.2(brs,1H), 5.92(s,1H), 4.479m,1H), 4.43(s,2H), 3.25(m,1H),2.17(s,3H), 2.10(s,6H), 1.58(m,2H), 1.47(m,2H), 0.90(t,6H) ppm.

EXAMPLE 131N2-(2,4-Dichloro-phenyl)-N4-(1-ethyl-propyl)-3,6-dimethyl-pyridine-2,4-diamine

[0414] The title compound was prepared by a method analogous to thatdescribed for Example 33. 1H NMR(CDCl₃) d 7.79(dd,1H), 7.30(d,1H),7.10(dd,1H), 6.53(brs,1H), 6.13(s,1H), 3.79(d,1H), 3.2-3.4(m,1H),2.36(s,3H), 1.92(s,3H), 1.4-1.6(m,4H), 0.93(t,6H) ppm.

EXAMPLE 132[2-(2,4-Dichloro-phenylamino)-4-(1-ethyl-propylamino)-6-methyl-pyridin-3-yl]-methanol

[0415] The title compound was prepared by reduction of the correspondingnicotinic acid derivative with BH₃.DMS in THF at reflux. 1H NMR(CDCl₃) d7.22(d,1H), 7.07(d,1H), 7.00(d,1H), 6.10(s,1H), 5.7(brs,1H), 4.4(s,2H),3.3 (m,1H), 2.35(s,3H), 2.02(s,3H), 1.4-1.6(m,4H), 0.92&0.91 (two setsof t,6H) ppm.

EXAMPLE 1332-[6-Methyl-3-nitro-2-(2,4,6-trimethyl-phenylamino)-pyridin-4-ylamino]-butan-1-ol

[0416] The title compound was prepared by heating2-[6-methyl-3-nitro-2-chloro-pyridin-4-ylamino]-butan-1-ol withtrimethylaniline in DMSO at 130° C. 1H NMR(CDCl₃) d 9.38(brs,1H),6.93(s,3H), 3.7-3.8(m,3H), 2.30(s,3H), 2.12(s,6H), 1.8(m,1H),1.65(m,1H), 1.02(t,3H) ppm

EXAMPLE 1342-[4-(1-Ethyl-propylamino)-2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyrimidin-5-yl]-propionicacid ethyl ester

[0417] 1H NMR(CDCl₃) d 6.85(s,2H), 5.16(d,1H), 4.49(q,IH),4.0-4.2(m,3H), 2.289s,3H0, 2.20(s,3H), 2.06(s,6H), 1.4-1.7(m,4H),1.44(d,3H), 1.21(t,3H), 0.93(t,3H), 0.87(t,3H) ppm.

EXAMPLE 135[3-Aminomethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin4-yl]-(1-ethyl-propyl)-amine

[0418] The title compound was prepared by a method analogous to thatdescribed for Example 75. mp. 117-119° C.; Anal. For C₂₁H₃₁N₃O. ⅓H₂0calc.: C,72.58; H, 9.18; N, 12.09; found: C, 72.93; H, 9.28; N, 12.02.

[0419] The following title compounds of Examples 136-138 were preparedby reacting[4-(1-ethyl-propylamino)-6-methyl-2-(4-halo-2,6-dimethyl-phenoxy)-pyridin-3-yl]-methanolwith thionyl chloride in benzene, concentrated to dryness, followed byreacting with potassium cyanide in DMSO at room temperature.

EXAMPLE 136[2-(4-Bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-pyridin-3-yl]-acetonitrile

[0420] 1H NMR(CDCl₃) d 7.2(s,2H), 6.1(S,1H), 3.82(d,1H), 3.7(s,2H),3.34(m,1H), 2.1(s,3H), 2.03(s,6H), 1.45-1.7(m,4H), 0.99(t,6H) ppm.

EXAMPLE 137[2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-pyridin-3-yl]-acetonitrilehydrogen chloride

[0421] 1H NMR(CDCl₃) d 7.08(s,2H), 6.2(s,1H), 4.92(d,1H), 3.45(m,1H),2.71(s,3H), 2.549m,2H), 2.14(s,6H), 1.7(m,2H), 1.40-1.6(m,4H),0.95(t,6H) ppm.

EXAMPLE 138[6-(1-Ethyl-propoxy)-2-methyl-pyrimidin-4-yl]-(2,4,6-trimethyl-phenyl)-amine

[0422] MP. 149-151° C., Anal. For C₂₀H₂₆N₄O calc.: C, 72.81; H, 8.68; N,13.41; found: C, 72.70; H, 8.86; N, 13.14

EXAMPLE 1392-[2-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-(S)-ylamino]-butan-1-ol

[0423] The title compound was prepared by heating the correspondingnicotinic acid derivative at 160-170° C. oil bath. 1H NMR (CDCl₃) d7.05(s,2H), 6.09(s,1H), 5.35(s,1H), 4.43(s,1H), 3.68(m,1H), 3.64(m,1H),3.29(m,1H), 2.30(s,3H), 2.09(s,6H), 1.60(m,1H), 1.47(m,1 H), 0.89(t,3H)ppm.

EXAMPLE 140[3-Aminomethyl-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-(S)-yl](1-chloromethyl-propyl)-amine

[0424] The title compound was prepared by reacting[2-[2-(4-chloro-2,6-dimethyl-phenoxy)-3-pyridin-4-(S)-ylamino]-butan-1-ol with thionyl chloride in benzene,concentrated to dryness, followed by reacting with NH₃(g) at roomtemperature. After standard workup procedure and silica gel columnchromatography, the title compound was obtained. 1H NMR(CDCl₃) d7.00(s,2H), 6.3(brs,1H), 6.07(s,1H), 4.0-4,2(m,2H), 3.9(brs,2H),3.5-3.8(m,3H), 2.12(s,3H), 2.03(s,6H), 1.6-1.9(m,2H), 1.00(t,3H) ppm

[0425] The following title compounds of Examples 254 and 255 wereprepared by reacting [2-(2-(4-chloro-2,6-dimethyl-phenoxy)-3-pyridin-4-(S)-ylamino]-butan-1-ol with thionyl chloride in benzene,concentrated to dryness, followed by reacting with an appropriate aminein THF at room temperature. After standard workup procedure and silicagel column chromatography, the title compound was obtained.

EXAMPLE 1412-[2-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-3-methylaminomethyl-pyridin-4-(S)-ylamino]-butan-1-ol

[0426] 1H NMR(CDCl₃) d 7.01(s,2H), 6.14(s,1H), 4.55(brs,1H),3.6-3.8(m,2H), 3.4(m,1H), 2.6(s,3H), 2.11 (s,3H), 2.02(brs,6H),1.65(m,2H), 0.97(t,3H)ppm.

EXAMPLE 1422-[3-Aminomethyl-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-(S)-ylamino]-butan-1-ol

[0427] 1H NMR(CDCl₃) d 6.999s,2H), 6.10(s,1H), 4.4.00(Abq,2H),3.5-3.75(m,2H), 3.4(m,1H), 2.73(brs,4H), 2.08(s,3H), 2.00(s,6H),1.58(m,4H), 0.94(t,3H) ppm.

[0428] The title compounds of the following Examples 143 through 149were prepared by bromination or chlorination of2-[2-(substituted-phenoxy)-6-methyl-pyridin-4-alkylamine with NBS or NCSin methylene chloride or chloroform at room temperature.

EXAMPLE 143[3-Bromo-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethyl-propyl)-amine

[0429] 1H NMR(CDCl₃) d 6.85(s,2H), 6.04(s,1H), 4.62(d,1H), 3.33(m,1H),2.27(s,3H), 2.13(s,3H), 2.08(s,6H), 1.5-1.7(m,2H), 0.95(t,3H) ppm.

EXAMPLE 1442-[3,5-Dibromo-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-ylamino]-butan-1-ol

[0430] 1H NMR(CDCl₃) d 7.02(s,2H), 4.34(m,1H), 3.6-3.8(m,2H),2.30(s,3H), 2.05(s,6H), 1.5-1.8(m,2H), 0.98(t,3H) ppm.

EXAMPLE 1452-[3-Bromo-6-(4-chloro-2,6-dimethyl-phenoxy)-2-methyl-pyridin-4-(S)-ylamino]-butan-1-ol

[0431] 1H NMR(CDCl₃) d 7.05(s,2H), 5.62(s,1H), 4.86(d,1H),3.55-3.7(m,2H), 3.3(m,1H), 2.428(s,3H), 2.09(s,6H), 1.4-1.7(m,3H),0.91(t,3H) ppm.

EXAMPLE 1462-(3-Bromo-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-(S)-ylamino]-butan-1-ol

[0432] 1H NMR(CDCl₃) d 7.02(s,2H), 6.14(s,1H), 4.81(d,1H),3.6-3.8(m,2H), 3.45(m,1H), 2.12(s,3H), 2.08(s,6H), 1.5-1.8(m,2H),1.00(t,3H) ppm.

EXAMPLE 1472-[3-Chloro-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-(S)-ylamino]-butan-1-ol

[0433] 1H NMR(CDCl₃) d 7.02(s,2H), 6.18(s,1H), 4.76(d,1H),3.6-3.8(m,2H), 3.45(m,1H), 2.13(s,3H), 2.07(s,6H), 1.5-1.8(m,2H),0.99(t,3H) ppm.

EXAMPLE 1482-[3,5-Dichloro-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-ylamino]-butan-1-ol

[0434] 1H NMR(CDCl₃) d 7.03(s,2H), 4.34(m,1H), 3.6-3.8(m,2H),2.40(s,3H), 2.05(s,6H), 1.5-1.8(m,2H), 0.99(t,3H) ppm.

EXAMPLE 1492-[3-Chloro-6-(4-chloro-2,6-dimethyl-phenoxy)-2-methyl-pyridin-4-(S)-ylamino]-butan-1-ol

[0435] 1H NMR(CDCl₃) d 7.05(s,2H), 5.66(s,1H), 4.86(brs,1H),3.5-3.8(m,2H), 3.3(m,1H), 2.38(s,3H), 2.09(s,6H), 1.4-1.7(m,3H),0.91(t,3H) ppm.

EXAMPLE 1502-(4-Chloro-2,6-dimethyl-phenoxy)-4-(S)-(4-ethyl-2-oxo-oxazolidin-3-yl)-6-methyl-nicotinonitrile

[0436] The title compound was prepared by reacting with2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-methyl-nicotinicacid with triphosgene/NEt₃ in THF. 1H NMR(CDCl₃) d 7.18(s,1H),7.06(s,2H), 5.00(m,1H), 4.64(t,1H), 4.23(dd,1H), 2.339s,3H), 2.08(s,6H),1.5-1.8(m,2H), 0.949t,3H) ppm.

EXAMPLE 1512-(2,4-Dimethoxy-phenylamino)-4-(1-methoxymethyl-propoxy)-6-methyl-nicotinicacid

[0437] 1H NMR(CDCl₃) d 8.3(brs,1H), 6.5(m,3H), 6.26(s,1H), 4.66(m,1H),3.92(s,3H), 3.85(s,3H), 3.66(m,2H), 3.43(s,3H), 2.52(s,3H), 1.91 (m,2H),1 .07(t,3H) ppm.

EXAMPLE 152 4-(1-Ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimidine-5-carbonitrile

[0438] 1H NMR(CDCl₃) d 6.92(s,2H), 6.45(s,1H), 5.22(m,1H), 2.29(s,6H),2.16(s,6H), 1.70(m,4H), 0.93(t,6H) ppm.

EXAMPLE 153 N-(1-Ethyl-propyl)-2,5-dimethyl-N′-(2,4,6-trimethyl-phenyl)-pyrimidine-4,6-diamine

[0439] 1H NMR(CDCl₃) d 8.9(s,1H), 6.85(s,2H), 4.95(d,1H), 4.21(m,1H),2.5(s,3H), 2.25(s,3H), 2.13(s,6H), 1.4-1.7(m,4H), 1.3(s,3H), 0.85(t,6H)ppm

EXAMPLE 1545-Chloro-N4-(1-ethyl-propyl)-2-methyl-N6-(2,4,6-trimethyl-phenyl)-pyrimidine-4,6-diamine

[0440] 1H NMR(CDCl₃) d 6.85(s,2H), 6.0(s,1H), 4.D(m,1H), 4.2(m,1H),2.3(s,3H), 2.22(,3H), 2.17(s,6H), 1.4-1.70(m,4H), 0.97(t,6H) ppm.

EXAMPLE 1555-Bromo-N-(1-ethyl-propyl)-2-methyl-N′-(2,4,6-trimethyl-phenyl)-pyrimidine-4,6-diamine

[0441] MP. 117-119° C., Anal. For C₁₉H₂₁BrN₄ calc.: C, 58.31; H, 6.95;N, 14.32; found: C, 58.43; H, 7.08; N, 14.23.

EXAMPLE 1564-(1-Ethyl-propylamino)-2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimidine-5-carboxylicacid

[0442] 1H NMR(CDCl₃) d 12.2(brs,1H), 11.1(brs,1H), 6.84(s,2H),4.18(m,1H), 2.38(s,3H), 2.18(s,3H), 2.15(s,6H), 1.56(m,4H), 0.90(t,6H)ppm.

EXAMPLE 157[4-(Cyclopropylmethyl-propyl-amino)-2-methyl-6-(2,4,6-trichloro-phenylamino)-pyrimidin-5-yl]-methanol

[0443] 1H NMR(CDCl₃) d 7.49s,2H), 4.95(s,2H), 4.92(s,1H), 3.28(brs,4H),2.359s,3H), 1.54(m,2H), 0.95(m,1H), 0.81(t,3H), 0.44(m,2H), 0.19(m,2H)ppm.

EXAMPLE 158 6-(1-Ethyl-propoxy)-2,N5,N5-trimethyl-N4-(2,4,6-trimethyl-phenyl)-pyrimidine-4,5-diamine

[0444] The title compound was prepared by methylation of 6-(1-ethyl-propoxy)-2-methyl-N4-(2,4,6-trimethyl-phenyl)-pyrimidine-4,5-diaminewith lithium bis(trimethylsilyl)amide in THF, followed by quenching withmethyl iodide. 1H NMR(CDCl₃) d 7.35(s,1H), 6.90(s,2H), 5.16(m,1H),2.73(s,6H), 2.29(s,3H), 2.27(s,3H), 2.18(s,6H), 1.6-1.8(m,4H),0.96(t,6H) ppm.

EXAMPLE 159[5-Bromo-6-(1-ethyl-propoxy)-2-methyl-pyrimidin-4-yl]-(2,4,6-trimethyl-phenyl)-amine

[0445] The title compound was prepared by reacting[5-bromo-6-(1-ethyl-propoxy)-2-methyl-pyrimidin-4-yl]-(2,4,6-trimethyl-phenyl)-aminewith 3-pentanol/NaH in THF at reflux overnight. After standard work-upand purification, the title compound was obtained as a white solid, mp.94-96° C. 1H NMR(CDCl₃) d 6.91(s,2H), 6.41(s,1H), 5.13(m,1H),2.29(s,3H), 2.26(,3H), 2.17(s,6H), 1.70(m,4H), 0.95(t,6H) ppm.

EXAMPLE 1604-(1-Ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimidine-5-carboxylicacid

[0446] To a solution of n-BuLi in THF was added a solution of[5-bromo-6-(1-ethyl-propoxy)-2-methyl-pyrimidin-4-yl]-(2,4,6-trimethyl-phenyl)-aminein THF at −78° C. After stirring for 10 minutes, CO₂(g) was added at−78° C. and stirred at that temperature for 1 hour, then graduallywarmed to room temperature. The resulting mixture was quenched withwater and adjusted to pH 2 to 3 and extracted with chloroform. Theorganic layer was separated, dried and concentrated to dryness. Theresidue was purified through silica gel column chromatography to givethe title compound as a solid, mp. 118-120° C., Anal. For C₂₀H₂₇N₃O₃calc.: C, 67.20; H, 7.61; N, 11.76; found: C, 67.25; H, 7.87; N, 11.48.

EXAMPLE 161[4-(1-Ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimidin-5-yl]-methanol

[0447] To a solution of4-(1-ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimidine-5-carboxylicacid in dry THF was added BH₃.DMS. The resulting mixture was heated atreflux. The mixture was quenched with dilute HCI and stirred for 30minutes;, adjusted pH to 7.5-8.5, then extracted with ethyl acetate. Theorganic layer was separated, dried and concentrated to give a crudematerial. The crude material was purified through silica gel columnchromatography to give the title compound as a solid, mp. 121-123° C.,Anal. For C₂₀H₂₉N₃O₂ calc. C, 69.94; H, 8.51; N, 12.23; found: C, 69.73;H, 8.47; N, 11.99.

EXAMPLE 162[6-(1-Ethyl-propoxy)-5-methoxymethyl-2-methyl-pyrimidin-4-yl]-(2,4,6-trimethl-phenyl)-amine

[0448] The title compound was prepared by reacting[4-(1-ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimidin-5-yl]-methanolwith NaH, followed by quenching with Mel. 1H NMR(CDCl₃) d 7.0(s,1H),6.89(s,2H), 5.12(m,1H), 4.62(s,2H), 3.33(s,3H), 2.28(s,3H0, 2.27(s,3H),2.14(s,6H), 1.66(m,4H), 0.91(t,6H) ppm.

EXAMPLE 163[5-Aminomethyl-6-(1-ethyl-propoxy)-2-methyl-pyrimidin-4-yl]-(2,4,6-trimethyl-phenyl)-amine

[0449] To a solution of[4-(1-ethyl-propoxy)-2-methyl-6-(2,4,6-trimethyl-phenylamino)-pyrimidin-5-yl]-methanolin anhydrous methylene chloride was added thionyl chloride. Afterstirring for 1 hour, the reaction mixture was concentrated to dryness.The residue was dissolved in dry THF and NH₃(g) was bubbled in. Thereaction mixture was quenched with water and extracted with ethylacetate. The reaction was worked-up and purified by standard procedureto give the title compound.

[0450] 1H NMR(CDCl₃) d 8.50(s,1H), 6.88(s,2H), 5.08(m,1H), 3.97(s,2H),2.279s,3H), 2.25(s,3H), 2.159s,6H), 1.74(brs,2H), 1.65(m,4H), 0.91(t,6H)ppm.

EXAMPLE 1647-(1-Ethyl-propoxy)-5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo[4,5-b]pyridin-2-ylamine

[0451] The title compound was prepared by reacting4-(1-ethyl-propoxy)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3-diaminewith BrCN in acetonitrile at room temperature overnight. The mixture wasquenched with water and adjusted to pH 8.0 with saturated sodiumbicarbonate and extracted with ethyl acetate. The organic layer wasseparated, dried and concentrated to give crude material. The materialwas purified through silica gel column chromatography to give the titlecompound as a white solid, mp. 159-161° C. 1H NMR(CDCl₃) d 7.05(s,2H),6.5(s,1H), 4.6(m,1H), 4.3(m,2H), 2.45(s,3H), 2.35(s,3H), 2.0(s,6H),1.7(m,4H), 1.0(t,6H) ppm.

EXAMPLE 1657-(1-Ethyl-propoxy)-5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo[4,5-b]pyridine

[0452] A mixture of4-(1-ethyl-propoxy)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3-diamine,trimethyl orthoformate, p-toluenesulfonic acid monohydrate in toluenewas heated at reflux using Dean-Stark apparatus for 24 hours. Themixture was heated at reflux overnight. The mixture was quenched withwater, sat. NaHCO₃, extracted with ethyl acetate. The organic layer wasseparated, dried (MgSO₄) and concentrated to dryness. Afterpurification, the title compound was isolated. Anal. For C₂₁H₂₉N₃O. ¼H₂Ocalc. C, 73.76; H, 8.10; N, 12.29; found: C, 73.22; H, 7.96; N, 12.42.

EXAMPLE 1667-(1-Ethyl-propoxy)-5-methyl-3-(2,4,6-trimethyl-phenyl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

[0453] The title compound was prepared by reacting4-(1-ethyl-propoxy)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3-diaminewith triphosgene, NEt₃ in THF at room temperature. A white solid wasisolated, mp. 184-186° C. Anal. For C₂₁H₂₇N₃O₂ calc. C, 71.36; H, 7.70;N, 11.89; found: C, 71.09; H, 7.75; N, 11.63.

EXAMPLE 167 7-(1-Ethyl-propoxy)-1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-one

[0454] The title compound was prepared by reacting7-(1-ethyl-propoxy)-5-methyl-3-(2,4,6-trimethyl-phenyl)-1,3-dihydro-imidazo[4,5-b]pyridin-2-onewith lithium bis(trimethylsilyl)amide, followed by quenching with methyliodide. Mp. 151-153° C. Anal. For C₂₂H₂₉N₃O₂. ¼H₂O calc. C, 71.03; H,7.99; N, 11.30; found: C, 71.29; H, 8.01; N, 11.03.

EXAMPLE 168(1-Ethyl-propyl)-[5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo[4,5-b]pyridin-7-yl]-amine

[0455] A mixture ofN-4-(1-ethyl-propyl)-6-methyl-N-2-(2,4,6-trimethyl-phenyl)-pyridine-2,3,4-triamine(250 mg, 0.77 mmol) , trimethyl orthoformate (0.081 g, 0.766 mmol),p-toluenesulfonic acid monohydrate (0.01 g) in benzene was heated atreflux using Dean-Stark apparatus for 24 hours. Benzene was removed andtoluene was added and an excess of trimethyl orthoformate (0.084 ml) wasadded to the reaction mixture. The mixture was heated at refluxovernight. The mixture was quenched with water, sat. NaHCO₃, extractedwith ethyl acetate. The organic layer was separated, dried (MgSO₄) andconcentrated to dryness. After purification, the title compound wasisolated as white crystals, mp 78-80° C.

EXAMPLE 169[2,5-Dimethyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo[4,5-b]pyridin-7-yl]-1-ethyl-propyl)-amine

[0456] A mixture ofN-4-(1-ethyl-propyl)-6-methyl-N-2-(2,4,6-trimethyl-phenyl)-pyridine-2,3,4-triamine(250 mg, 0.77 mmol) , trimethyl orthoacetate (0.184 g, 1.532 mmol),p-toluenesulfonic acid monohydrate (0.01 g) in toluene was heated atreflux using Dean-Stark apparatus for 3 hours. The mixture was quenchedwith water, brine, extracted with ethyl acetate. The organic layer wasseparated, dried (MgSO₄) and concentrated to dryness. Afterpurification, the title compound was obtained as a white crystal, mp101-103° C. Anal. For C₂₂H₃₀N₄ calc. C, 75.39; H, 8.63; N, 15.98; found,C, 75.44; H, 8.95; N, 15.95.

EXAMPLE 170N7-(1-Ethyl-propyl)-5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-imidazo[4,5-b]pyridine-2,7-diamine

[0457] The title compound was prepared by reactingN4-(1-ethyl-propyl)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3,4-triaminewith BrCN in acetonitrile at room temperature overnight. The mixture wasquenched with water and adjusted to pH 8.0 with saturated sodiumbicarbonate and extracted with ethyl acetate. The organic layer wasseparated, dried and concentrated to give crude material. The materialwas purified through silica gel column chromatography to give the titlecompound as a brown solid, mp. 158-160° C.; Anal. For C₂₁H₂₉N₅ ¼H₂Ocalc. C, 70.85; H, 8.35; N, 19.67; found: C, 71.07; H, 8.30; N, 19.63.

EXAMPLE 1716-(1-Ethyl-propylamino)-2,7-dimethyl-9-(2,4,6-trimethyl-phenyl)-7,9-dihydro-purin-8-one

[0458] The title compound was prepared by methylation of6-(1-ethyl-propylamino)-2-methyl-9-(2,4,6-trimethyl-phenyl)-7,9-dihydro-purin-8-onewith lithium bis(trimethylsilyl)amide in THF, followed by quenching withmethyl iodide. 1H NMR(CDCl₃) d 6.98(s,2H), 4.45(d,1H), 4.3(m,1H),3.7(s,3H), 2.4(s,3H), 2.3(s,3H), 2.1(s,6H), 1.5-1.8(m,4H), 1.0(t,6H)ppm.

EXAMPLE 1726-(1-Ethyl-propoxy)-2,7-dimethyl-9-(2,4,6-trimethyl-phenyl)-7,9-dihydro-purin-8-one

[0459] The title compound was prepared by methylation of6-(1-Ethyl-propoxy)-2-methyl-9-(2,4,6-trimethyl-phenyl)-7,9-dihydro-purin-8-onewith lithium bis(trimethylsilyl)amide in THF, followed by quenching withmethyl iodide. 1H NMR(CDCl₃) d7.00(s,2H), 5.31(m,1H), 3.66(s,3H),2.479s,3H), 2.33(s,3H), 2.06(s,6H), 1.79(m,4H), 1.01(t,6H) ppm.

EXAMPLE 173[2-(4-Methoxy-2,6-dimethyl-phenoxy)-6-methyl-3-nitro-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine

[0460] 1H NMR(CDCl₃) d 7.71(d,1H), 6.57(s,2H), 6.21(s,1H), 3.76(s,3H),3.59(m,1H), 3.48(m,1H), 3.45(m,1H), 3.37(s,3H), 2.13(s,3H), 2.08(s,6H),1.6-1.8(m,4H), 0.86(t,3H) ppm.

EXAMPLE 174(1-Ethyl-propyl)-[2-(4-methoxy-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin4-yl]-amine

[0461] 1H NMR(CDCl₃) d 6.64(s,2H), 6.12(s,1H), 3.82(s,3H), 3.36(m,1H),2.26(s,3H), 2.13(s,6H), 2.10(s,3H), 1.5-1.8m,4H), 0.99(t,6H).

EXAMPLE 1752-[2-(4-Methoxy-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-ylamino]-butan-1-ol

[0462] 1H NMR(CDCl₃) d 6.64(s,2H), 6.13(s,1H), 4.10(m,1H), 3.76(s,3H),3.7-3.8(m,21H, 3.57(m,1H), 2.21(s,3H), 2.19(s,6H), 2.12(s,3H),1.6-1.8(m,2H), 1.04(t,3H) ppm.

EXAMPLE 176sec-Butyl-[3-methoxy-2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-pyridin4-yl]-amine

[0463] 1H NMR(CDCl₃) d 6.64(s,2H), 6.13(s,1H), 4.51(d,1H), 3.92(s,3H),3.82(s,3H), 3.469m, 1H), 2.18(s,3H), 2.15(s,6H), 1.60(m,2H), 1.26(d,3H),1.00(t,3H) ppm.

EXAMPLE 1772-(4-Chloro-2,6-dimethyl-phenoxy)-4-(4-ethyl-oxazolidin-3-yl)-3,6-dimethyl-pyridine

[0464] 1H NMR(CDCl₃) d 7.07(s,2H), 6.36(s,1H), 4.98(m,1H), 4.78(m,1H),4.23(m,1H), 3.83(m,1H), 3.71(m,1H), 2.28(s,3H), 2.20(s,3H), 2.09(s,6H),1.81(m,1H), 1.58(m,1lH), 0.98(t,3H) ppm.

EXAMPLE 1784-(4-Ethyl-oxazolidin-3-yl)-2-(4-methoxy-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridine

[0465] 1H NMR(CDCl₃) d 6.65(s,2H), 6.36(s,1H), 4.98(m,1H), 4.77(m,1H),4.23(m,1H), 3.83(s,3H), 3.71(m,1H), ), 2.29(s,3H), 2.22(s,3H),2.119(s,6H), 1.82(m,1H), 1.56(m,1H), 0.99(t,3H) ppm

EXAMPLE 1792-(4-Methoxy-2,6-dimethyl-phenoxy)-N%4&-(1-methoxymethyl-propyl)-6-methyl-pyridine-3,4-diamine

[0466] 1H NMR(CDCl₃) d 6.64(s,2H), 6.16(s,1H), 4.3(m,1H), 3.82(s,3H),3.6-3.8(m,2H), 3.42(s,3H), 3.2(brs,2H), 2.18(s,3H), 2.13(s,6H),1.6-1.8(m,2H), 1.03(t,3H) ppm.

EXAMPLE 1803-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-hydroxymethyl-6-methyl-pyridin4-ylamino]-pentan-2-ol

[0467] 1H NMR(CDCl₃) d 7.01(s,2H), 6.16(s,1H), 5.19(d,1H), 4.94(m,2H),3.88(m,1H), 3.27(m,1H), 2.11(s,3H), 2.05(s,6H), 1.73(m,1H), 1.57(m,1H),1.24(d,3H), 0.97(t,3H)ppm.

EXAMPLE 1812-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-oxo-propylamino)-6-methyl-nicotinicacid methyl ester

[0468] 1H NMR(CDCl₃) d 8.63(d,1H), 7.01(s,2H), 5.90(s,1H), 3.95(m,1H),3.90(s,3H)., 2.08(s,3H), 2.05(s,3H), 2.03(s,6H), 1.8-2.0(m,2H),1.00(t,3H) ppm.

EXAMPLE 1823-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-methoxymethyl-6-methyl-pyridin-4-ylamino]-pentan-2-ol

[0469] 1H NMR(CDCl₃) d 7.08(s,2H), 6.21(s,1H), 5.40(brs,1H), 4.83(q,2H),3.91(m,1H), 3.40(s,3H), 3.33(m,1H), 2.20(s,3H), 2.10(s,6H), 1.78(m,1H),1.58(m,1H), 1.29(d,3H), 1.01(t,3H) ppm.

EXAMPLE 1833-[2-(4-Methoxy-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-ylamino]-pentan-2-ol

[0470] 1H NMR(CDCl₃) d 6.66(s,2H), 6.27(s,1H), 4.05(m, 1H), 3.82(s,3H),3.38(m, 1H), 2.35(s,3H), 2.21(s,3H), 2.14(s,6H), 1.6-1.9(m,2H),1.30(m,3H), 1.01(t,3H)ppm.

EXAMPLE 1844-sec-Butylamino-2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-nicotinicacid methyl ester

[0471] 1H NMR(CDCl₃) d 8.01(d,1H), 6.58(s,2H), 6.06(s,1H), 3.85(s,3H),3.77(s,3H), 2.10(s,3H), 2.07(s,6H), 1.21(d,3H0, 0.97(t,3H) ppm.

EXAMPLE 1852-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-hydroxy-2-methyl-propylamino)-6-methyl-nicotinicacid methyl ester

[0472] 1H NMR(CDCl₃) d 8.28(d,1H), 7.06(s,2H), 6.32(s,1H), 3.92(s,3H),3.41(m,1H), 2.14(s,3H), 2.12(s,6H), 1.91(m,1H), 1.44(m,1H), 1.33(s,3H),1.30(s,3H0, 0.99(s,3H) ppm.

EXAMPLE 1864-(1-Hydroxymethyl-propylamino)-2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-nicotinicacid methyl ester

[0473] 1H NMR(CDCl₃) d 8.13(d,1H), 6.63(s,2H), 6.21(s,1H), 3.91(s,3H0,3.82(s,3H0, 3.81(m,2H), 3.59(m,1H), 2.16(s,3H), 2.12(s,6H),1.6-1.859m,2H), 1.05(t,3H) ppm.

EXAMPLE 1872-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-3-methylsulfanyl-propylamino)-6-methyl-nicotinicacid methyl ester

[0474] A mixture of2-(4-chloro-2,6-dimethyl-phenoxy)-4-chloro-6-methyl-nicotinic acidmethyl ester and L-methioninol in N-methyl-2-pyrodone (NMP) was heatedin a 134° C. oil bath for 3 hr. Standard work-up procedure andpurification provided the title compound. 1H NMR(CDCl₃) d 8.25(d,1H),7.02(s,2H), 6.30(s,1H), 3.85(s,3H), 3.6-3.9(m,3H), 2.5-2.7(m,2H),2.14(s,3H), 2.1 0(s,3H), 2.06(s,6H), 1.8-2.1 (m,2H)ppm.

EXAMPLE 1882-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-4-(S)-(tetrahydro-furan-3-ylamin-nicotinicacid methyl ester

[0475] To a solution of{3-[2-(4-chloro-2,6-dimethyl-phenoxy)-3-methoxycarbonyl-6-methyl-pyridin-4-ylamino]-4-hydroxy-butyl}-dimethyl-sulfoniumiodide in dry THF was added t-BuOK at −10° C. The mixture was stirred at−10° C. until all starting material was consumed. Standard work-upprocedure and silica gel purification gave the title compound.

[0476] 1H NMR(CDCl₃) d 8.25(d,1H), 7.01(s,2H), 6.05(s,1H), 4.11(m,1H),3.9-4.1(m,2H), 3.8-3.9(m,1H), 3.86(s,3H), 3.73(m,1H), 2.2-2.4(m,1H),2.11(s,3H), 2.05(s,6H), 1.95(m,1H) ppm.

EXAMPLE 189{3-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3-methoxycarbonyl-6-methyl-pyridin-4-ylamino]-4-hydroxy-butyl}-dimethyl-sulfoniumiodide

[0477] A mixture of2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-3-methylsulfanyl-propylamino)-6-methyl-nicotinicacid methyl ester and Mel in EtOAc was heated at reflux in a sealedtube. The mixture was concentrated to dryness and triturated withdiethyl ether to give the title compound. 1H NMR(CD₃OD) d 7.11(s,2H),6.61(s,1H), 4.00(m,1H), 3.86(s,3H), 3.6-3.9(m,3H), 2.95(d,6H),2.5-2.7(m,2H), 2.22(s,3H), 2.07(s,6H), 1.8-2.1(m,2H)ppm.

EXAMPLE 1904-(1-Hydroxymethyl-3-methylsulfanyl-propylamino)-2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-nicotinicacid methyl ester

[0478] 1H NMR(CDCl₃) d 8.15(d,1H), 6.58(s,2H), 6.28(s,1H), 3.85(s,3H),3.76(s,3H), 3.6-3.9(m,3H), 2.5-2.7(m,2H), 2.12(s,3H), 2.09(s,3H),2.07(s,6H), 1.8-2.1(m,2H)ppm.

EXAMPLE 1914-(1-Hydroxymethyl-propylamino)-2-(4-methoxy-2,6-dimethyl-phenoxy)-6,N-dimethyl-nicotinamide

[0479] 1H NMR(CDCl₃) d 9.84(d,1H), 8.31(m,1H), 6.66(s,2H), 6.29(s,1H),3.81(s,3H), 3.5-3.9(m,3H), 2.98(d,3H), 2.15(s,3H), 2.12(s,6H),1.6-1.8(m,2H), 1.05(t,3H)ppm.

EXAMPLE 1924-sec-Butylamino-2-(4-methoxy-2,6-dimethyl-phenoxy)-6,N-dimethyl-nicotinamide

[0480] 1H NMR(CDCl₃) d 9.77(brs,1H), 8.22(brs,1H), 6.61(s,2H),6.11(s,1H), 3.78(s,3H), 3.45(m,1H), 2.93(d,3H), 2.10(s,3H), 2.07(s,6H),1.5-1.7(m,2H), 1.23(m,3H), 0.98(t,3H)ppm.

EXAMPLE 1932-(4-Methoxy-2,6-dimethyl-phenoxy)-6-methyl-4-(tetrahydro-furan-3-ylamino)-nicotinicacid methyl ester

[0481] 1H NMR(CDCl₃) d 8.28(d,1H), 6.63(s,2H), 6.09(s,1H), 4.15(m,1H),3.98-4.1(m,2H), 3.8-3.98(m,1H), 3.90(s,3H), 3.81(s,3H), 3.76(m,1H),2.32-2.36(m,1H), 2.19(s,3H), 2.11(s,6H), 1.95(m,1 H) ppm.

EXAMPLE 1944-sec-Butylamino-2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-nicotinamide

[0482] 1H NMR(CDCl₃) d 9.74(ds,1H), 8.05(brs,1H), 6.65(s,2H),6.16(s,1H), 5.55(brs,1H), 3.83(s,3H), 3.51(m,1H), 2.16(s,3H),2.12(s,6H), 1.5-1.7(m,2H), 1.26(d,3H), 1.02(t,3H)ppm.

[0483] The following Examples 195-256 relate to other compounds offormula I of the invention, wherein R₄ is —COOCH₃:

[0484] The following title compounds of Examples 195-209 were preparedby the method analogous to that described in Example 13 starting with ana 4-chloro-2-(substituted-phenoxy)-6-methyl-nicotinic acid methyl esterand with an appropriate amine:

EXAMPLE 195 2-(4-Ethoxy-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-3-methylsulfanyl-propylamino)-6-methyl-nicotinic acidmethyl ester

[0485] 1H NMR (CDCl₃) d 8.35(d, 1H), 6.60(s, 2H), 6.41(s, 1H), 4.03(q,2H), 3.90(m, 1H), 3.86(s, 3H), 3.75(m, 2H), 2.60(, 2H), 2.21(s, 3H),2.11(s, 3H), 2.09(s, 6H), 2.03(m, 1H), 1.88(m, 1H), 1.40(t, 1.39)ppm

EXAMPLE 1964-(1-Hydroxymethyl-3-methylsulfanyl-propylamino)-2-[4-(2-methoxy-ethoxy)-2,6-dimethyl-phenoxy]-6-methyl-nicotinicacid methyl ester

[0486] 1H NMR(CDCl₃) d 8.38(d, 1H), 6.64(s, 2H), 6.42(s, 1H), 4.10(m,2H), 3.92(m, 1H), 3.86(s, 3H), 3.73(m, 5H), 3.45(s, 3H), 2.60(m, 2H),2.22(s, 3H), 2.13(s, 3H), 2.09(s, 6H), 1.87(m, 2H)ppm

EXAMPLE 1972-(2,6-Dimethyl-4-trifluoromethoxy-phenoxy)-4-(1-hydroxymethyl-3-methylsulfanyl-propylamino)-6-methyl-nicotinicacid methyl ester

[0487] 1H NMR(CDCl₃) d 8.21 (br d, 1H, J=8 Hz), 6.91 (s, 2H), 6.28 (s,1H), 3.87 (s, 3H), 3.84 (m, 1H), 3.70-3.76 (m, 2H), 2.53-2.68 (m, 2H),2.11 (m, 12H), 1.88-2.06 (m, 2H).

EXAMPLE 1982-(4-Chloro-2,6-dimethyl-phenoxy)-4-(R)-(1-hydroxymethyl-3-methylsulfanyl-propylamino)-6-methyl-nicotinicacid methyl ester

[0488] C₂₁H₂₇ClN₂O4_(s): MS: M+1 [439.2]

EXAMPLE 1992-(4-Chloro-2,6-dimethoxy-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-methyl-nicotinicacid methyl ester

[0489] 1H NMR(CDCl₃) d 8.29 (d, 1H, J+8 Hz), 6.63 (s, 2H), 6.23 (s, 1H),3.86 (s, 3H), 3.74 (s, 6H), 3.69-3.72 (m, 1H), 3.62-3.66 (m, 1H),3.52-3.58 (m, 1H), 2.83 (s, 1H), 2.13 (s, 3H), 1.70-1.77 (m, 1H),1.54-1.61 (m, 1H), 0.99 (t, 3H, J=7 Hz)

[0490] 13C NMR(CDCl₃) d.169.75, 158.50, 153.43, 130.15, 106.96, 101.49,64.67, 56.95, 56.12, 56.05, 52.18, 46.05, 24.92, 10.67

EXAMPLE 2002-(4-Chloro-2,6-dimethoxy-phenoxy)-4-(1-hydroxymethyl-3-methylsulfanyl-propylamino)-6-methyl-nicotinicacid methyl ester

[0491] 1H NMR(CDCl₃) d 8.39 (br d, 1H, J=7 Hz), 6.64 (s, 2H), 6.30 (s,1H), 3.87 (s, 3H), 3.75 (s, 6H), 3.36-3.39 (m, 1H), 2.84 (s, 1H),2.53-2.70 (m, 2H), 2.35-2.39 (m, 1H), 2.14 (d, 3H, J=9 Hz), 1.94-2.07(m, 2H), 1.79-1.92 (m, 2H) ppm. APCl+m/z=471.2 (M+1), 473.2 (M+3)

EXAMPLE 2012-(4-Chloro-2,6-dimethyl-phenoxy)-4-[(1-hydroxymethyl-propyl)-methyl-amino]-6-methyl-nicotinicacid methyl ester EXAMPLE 2024-(1-Ethyl-propylamino)-2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-nicotinicacid methyl ester

[0492] APCI M=![387.3], 1H NMR(CDCl₃)

EXAMPLE 2032-(2,6-Dimethyl-4-[1,3,4]oxadiazol-2-yl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-nicotinicacid methyl ester

[0493] 1H NMR(CDCl₃) d 8.43 (s, 1H), 8.22 (br d, ½H), 7.80 (s, 2H), 6.12(s, 1H), 3.88 (s, 3H), 3.3-3.4 (m, 1H), 2.15-2.2 (m, 9H), 1.5-1.7 (m,4H), 0.967 (t, 6H, J=7 Hz)

[0494] 13C NMR(CDCl₃) d.

[0495] APCl+m/z=425.3 (M+1)

EXAMPLE 2042-(4-Chloro-2-methoxy-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-nicotinicacid methyl ester

[0496] 1H NMR(CDCl₃) d 8.14 (d, 1H, J=8 Hz), 6.90-7.26 (m, 3H), 6.14 (s,1H), 3.82 (s, 3H), 3.77 (s, 3H), 3.32-3.73 (m, 1H), 2.17 (s, 3H),1.49-1.67 (m, 4H), 0.94 (t, 6H, J=7 Hz) ppm.

EXAMPLE 2054-(1-Hydroxymethyl-propylamino)-2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-nicotinicacid methyl ester

[0497] 1HNMR(CDCl₃) 8.21(d, 1H), 6.60(s, 2H), 6.30(s, 1H), 3.87(s, 3H),3.78(s, 3H), 3.65(m, 3H), 2.17(s, 3H0, 2.09(s, 6H), 1.75(m, 1H), 1.61(m,1H), 1.01(t, 3H)ppm

EXAMPLE 2062-(4-Chloro-2-fluoro-6-methoxy-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-nicotinicacid methyl ester

[0498] APCl+m/z=411 (M+1), 413 (M+3)

EXAMPLE 2072-(4-Chloro-2-methoxy-6-methyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-nicotinicacid methyl ester

[0499] 1H NMR(CDCl₃) d 8.16-8.20 (m, 1H), 6.82 (d, 1H, J=1.5 Hz), 6.78(d, 1H, J=1.5 Hz), 6.09 (s, 1H), 3.85 (s, 3H), 3.72 (s, 3H), 3.3-3.8 (m,1H), 2.12 (s, 3H), 1.51-1.67 (m, 4H), 0.95 (t, 6H, J=7 Hz)ppm.

[0500] APCl+m/z=407.2 (M+1), 409.2 (M+3)

EXAMPLE 2082-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-methoxymethyl-propylamino)-6-methyl-nicotinicacid methyl ester

[0501] 1H NMR(CDCl₃) d 8.2(d,1H), 7.02(s,2H), 6.14(s,1H), 3.87(s,3H),3.6(m,1H), 3.56(m,1H), 3.4(m,1H), 3.39(s,3H), 2.10(s,3H), 2.07(s,6H),1.78(m,1H), 1.61(m,1H), 1.00(t,3H)ppm.

EXAMPLE 2092-(4-Bromo-2-methoxy-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-nicotinicacid methyl ester

[0502] 1H NMR(CDCl₃) d 8.14 (br d, 1H), 7.03-7.07 (m, 2H), 6.88 (d, 1H,J=8 Hz), 6.14 (s, 1H), 3.82 (s, 3H), 3.77 (s, 3H), 3.32-3.37 (m, 1H),2.18 (s, 3H), 1.49-1.68 (m, 4H), 0.94 (t, 6H, J=7 Hz)

[0503] APCI+m/z=437.1 (M+1), 439.1 (M+3)

EXAMPLE 2102-(4-Chloro-2-hydroxy-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-nicotinicacid methyl ester

[0504] The title compound was prepared by reacting2-(4-chloro-2-methoxy-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-nicotinicacid methyl ester with BBr₃ in methylene chloride at rt until allstarting material was consumed. Standard work-up procedure gave thetitle compound.

[0505] APCI+m/z=379.2 (M+1), 381.2 (M+3)

EXAMPLE 2112-(4-Chloro-2-ethoxy-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-nicotinicacid methyl ester

[0506] 1H NMR(CDCl₃) d 8.10 (br d, 1H), 6.98 (d, 1H, J=8 Hz), 6.86-6.91(m, 2H), 6.14 (s, 1H), 3.97 (q, 2H, J=7 Hz), 3.83 (s, 3H), 3.32-3.37 (m,1H), 2.16 (s, 3H), 1.50-1.68 (m, 4H), 1.19 (t, 3H, J=7 Hz), 0.94 (t, 6H,J=7 Hz) ppm. APCI+m/z=407.1 (M+1), 409.1 (M+3)

EXAMPLE 2124-(2-Hydroxy-1-hydroxymethyl-ethylamino)-2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-nicotinicacid methyl ester

[0507] 1HNMR(CDCl₃) 8.42(d, 1H), 7.02(s, 2H), 6.17(s, 1H), 3.89(m, 2H),3.86(s, 3H), 3.85(m, 2H), 3.67(m, 1H), 2.10(s, 3H), 2.05(s, 6H)ppm

EXAMPLE 2134-(1-Carboxy-propylamino)-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-nicotinic acid methyl ester

[0508] A mixture of2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-formyl-propylamino)-6-methyl-nicotinicacid methyl ester, 2-methyl-2-butene, excess NaClO₂, and NaH₂PO₄ wasstirred at rt for 15 min. The mixture was quenched with sat. sodiumbicarbonate and extracted with hexane. The aqueous layer was acidifiedto pH 4 and extracted twice with diethyl ether. The organic layer wasseparated, dried and concentrated to give the title compound. The crudematerial was purified by silica gel column chromatography to give thedesired product as a white crystal after recrystallization. Anal. ForC₂₀H₂₃N₂O₅Cl calc., C, 59.04; H, 5.70; N, 6.89; found C, 59.29; H, 5.73;N, 6.83.

EXAMPLE 2144-(1-Carboxy-propylamino)-2-(4-chloro-2,6-dimethyl-phenoxy)-5-chloro-6-methyl-nicotinicacid methyl ester

[0509] The title compound was prepared by the method analogous to thatin Example 213, except with stirring overnight in the absence of2-methyl-2-butene instead of a 15 minute reaction time.

EXAMPLE 215 4-(1-Carbamoyl-propylamino)-5-chloro-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-nicotinic acid methyl ester

[0510] A mixture of4-(1-carboxy-propylamino)-2-(4-chloro-2,6-dimethyl-phenoxy)-5-chloro-6-methyl-nicotinicacid methyl ester with excess of thionyl chloride in methylene chlorideand stirred for 15 min. The mixture was concentrated to dryness. Theresidue was diluted with methylene chloride and ammonium was bubbledinto the reaction mixture. After stirring for 30 min, the mixture wasquenched with water, extracted with methylene chloride. The organiclayer was concentrated to dryness. The residue was purified by silicagel Biotage to give the title compound. 1HNMR(CDCl₃) 7.02(s, 2H),6.34(s, 1H), 5.92(d, 1H), 5.81(s, 1H), 4.05(m, 1H), 3.92(s, 3H), 2.27(s,3H), 2.05(s, 6H), 1.80(m, 2H), 1.00(t, 3H)ppm

[0511] The following compounds (Examples 216-223)were prepared by amethod similar to that described above starting with a carboxylic acidand excess of thionyl chloride in methylene, concentration, quenchingwith ammonium, alkylamine, dialkylamine or alkanol (eg., methanol,ethanol, etc.):

EXAMPLE 2162-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-methoxycarbonyl-propylamino)-6-methyl-nicotinicacid methyl ester

[0512] 1HNMR(CDCl₃) 8.52(d, 1H), 7.02(s, 2H), 5.97(s, 1H), 4.09(m,1H),3.89(s, 3H), 3.78(s, 3H), 2.09(s, 3H), 2.06(s, 6H), 1.98(m, 2H),1.04(t, 3H)ppm

EXAMPLE 2174-(1-Carbamoyl-propylamino)-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-nicotinicacid methyl ester

[0513] 1H NMR(CDCl₃)d 8.56(d, 1H), 7.04(s, 2H), 6.38(s, 1H), 6.12(s,1H), 5.44(s, 1H)., 3.91(s, 3H), 3.88(m, 1H), 2.15(s, 1H), 2.07(s, 1H),1.95(m, 2H), 1.24(t, 3H) ppm

EXAMPLE 218 2-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-4-(1-methylcarbamoyl-propylamino)-nicotinic acid methyl ester

[0514] 1HNMR(CDCl₃) 8.49(d, 1H), 7.05(s, 2H), 6.48(s, 1H), 6.08(s, 1H),3.91(s, 3H), 3.90(m, 1H), 2.83(m, 3H), 2.15(s, 3H), 2.08(m, 6H), 1.08(t,3H)ppm

EXAMPLE 2195-Chloro-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-4-(1-methylcarbamoyl-propylamino)-nicotinicacid methyl ester

[0515] 1HNMR(CDCl₃) 7.02(s, 2H), 6.42(m, 1H), 5.80(m, 1H), 3.96(m, 1H),3.89(s, 3H), 2.86(d, 3H), 2.28(s, 3H), 2.04(m, 6H), 1.78(m, 2H), 0.98(t,3H)ppm

EXAMPLE 2202-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-dimethylcarbamoyl-propylamino)-6-methyl-nicotinicacid methyl ester

[0516] 1HNMR(CDCl₃) 8.67(d, 1H), 7.02(s, 2H), 5.97(s, 1H), 4.39(m, 1H),3.89(s, 3H), 3.13(s, 3H), 3.02(s, 3H), 2.13(s, 3H), 2.06(m, 6H), 1.92(m,2H), 1.00(t, 3H) ppm

EXAMPLE 2215-Chloro-2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-dimethylcarbamoyl-propylamino)-6-methyl-nicotinicacid methyl ester

[0517] 1HNMR(CDCl₃) 7.02(s, 2H), 6.42(d, 1H), 4.66(m, 1H), 3.93(s, 3H),3.06(s, 3H), 3.01 (s, 3H), 2.27(s, 3H), 1.82(m, 2H), 0.90(t, 3H) ppm

EXAMPLE 2222-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-4-[1-(pyrrolidine-1-carbonyl)-propylamino]-nicotinicacid methyl ester

[0518] 1HNMR(CDCl₃) 8.61(d, 1H), 7.02(s, 2H), 5.97(s, 1H), 4.20(m, 1H),3.89(s, 3H), 3.59(m, 4H), 2.13(s, 3H), 2.01(m, 12H), 1.02(t, 3H)ppm

EXAMPLE 223 5-Chloro-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-4-[1-pyrrolidine-1-carbonyl)-propylamino]-nicotinicacid methyl ester

[0519] 1HNMR(CDCl₃) 7.02(s, 2H), 6.41(d, 1H), 4.44(m, 1H), 3.93(s, 3H),3.56(m, 2H), 3.47(m, 2H), 2.26(s, 3H),2.06(s, 6H), 2.00(m, 6H), 0.91(t,3H)ppm

EXAMPLE 2242-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-4-(1-methylaminomethyl-propylamino)-nicotinicacid methyl ester

[0520] A mixture of2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-formyl-propylamino)-6-methyl-nicotinicacid methyl ester (67 mg, 0.17 mmol) in dichloroethane (2 ml) wastreated with methylamine, 1 drop of acetic acid, anhydrous Na₂SO₄ andsodium cyanoborohdride and stirred at rt. overnight. The mixture wasquenched with water, extracted with methylene chloride. The organiclayer was separated, dried, concentrated, and purified by silica gelBiotage using methylene chloride to 5% methanol in methylene chloride aseluent to give the title compound as an off-white solid. 1HNMR(CDCl₃)8.07(d, 1H), 7.02(s, 2H), 6.29(s, 1H), 3.87(s, 3H), 3.80(m, 1H), 2.88(m,2H), 2.56(s, 3H), 2.11(s, 3H), 2.06(s, 6H), 1.63(m, 2H), 0.99(t, 3H)ppm

[0521] The following compounds (Examples 225-227) were prepared in asimilar reductive amination method as described in Example 224.

EXAMPLE 2252-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-4-(1-pyrrolidin-1-ylmethyl-propylamino)-nicotinicacid methyl ester

[0522] 1HNMR(CDCl₃) 8.11(d, 1H), 6.99(s, 2H), 6.12(s, 1H), 3.84(s, 3H),3.54(m, 1H), 3.43(m, 2H), 2.56(m, 4H), 2.07(s, 3H), 2.06(s, 6H), 1.84(m,6H), .96(t, 3H)ppm

EXAMPLE 2262-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-cyclopropylaminomethyl-propylamino)-6-methyl-nicotinicacid methyl ester

[0523] 1H NMR(CDCl₃) d 8.07(d, 1H), 7.02(s, 2H), 6.31(s, 1H), 3.87(s,3H), 3.79(m, 1H), 2.96(m, 1H), 2.36(m, 1H), 2.11(s, 3H), 2.07(s, 6H),1.83(m, 1H), 1.61(m, 1H), 0.99(t, 3H), 0.98(m, 4H)ppm

EXAMPLE 227 2-(4-Chloro-2,6-dimethyl-phenoxy)-4-{1-[(cyclopropylmethyl-amino)-methyl]-propylamino}-6-methyl-nicotinicacid methyl ester

[0524] 1H NMR(CDCl₃) d 8.07(d, 1H), 7.02(s, 2H), 6.55(s, 1H),4.12(m,1H), 3.88(s, 3H), 3.06(d, 2H), 2.87(m, 2H), 2.16(s, 3H),2.05(s,6H), 2.03(m,1H), 1.69(m, 1H)1.25(m, 1H)1.03(t, 3H), 0.66(m, 2H), 0.38(m,2H)ppm

EXAMPLE 2282-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethylaminomethyl-propylamino)-6-methyl-nicotinicacid methyl ester

[0525] A solution of2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-methanesulfonyloxymethyl-propylamino)-6-methyl-nicotinicacid methyl ester in acetonitrile was treated with sodium iodide,ethylamine and triethylamine. The resulting mixture was heated to 70° C.overnight, then 85° C. for 6 hrs, then 100° C. overnight until ticshowed no starting material. The resulting mixture was quenched withwater and extracted with ethyl acetate. The organic layer was separated,dried, concentrated, and purified to give the title compound as an oil.1H NMR(CDCl₃) d 8.06(d, 1H), 7.02(s, 2H), 6.31(s, 1H), 3.88(s, 3H),3.86(m,1H), 2.85(m, 4H), 2.12(s,3H), 2.07(s, 6H), 1.64(m, 1H), 1.60(m,1H), 1.27(m, 3H), .99(t, 3H)

EXAMPLE 2292-(4-Chloro-2,6-dimethyl-phenoxy)-4-{1-[(ethyl-methyl-amino)-methyl]-propylamino}-6-methyl-nicotinicacid methyl ester

[0526] 1H NMR(CDCl₃) d 8.18 (d, 1H), 7.02(s, 2H), 6.19(m, 1H), 3.86(s,3H), 3.56(m, 3H), 3.37(m, 2H), 2.11 (s, 3H), 2.07(s, 6H), 1.80(m, 1H),1.60(m,2H),1.25(m,4H), 0.97(t, 3H) ppm

EXAMPLE 2304-(1-Butylaminomethyl-propylamino)-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-nicotinicacid methyl ester

[0527] 1H NMR(CDCl₃) d 8.07(d, 1H) 7.02(s, 1H), 6.25(s, 1H), 3.87(s,3H), 3.79(m, 1H), 2.79 (m, 2H), 2.69(m ,2H), 2.10(s, 3H), 2.07(s, 6H),1.75(m, 2H), 1.57(m, 4H), 1.00(t, 3H), 0.92(t, 6H)ppm

EXAMPLE 2312-(4-Chloro-2,6-dimethyl-phenoxy)-4-{1-[(cyclopropylmethyl-propyl-amino)-methyl]-propylamino}-6-methyl-nicotinicacid methyl ester

[0528] 1H NMR(CDCl₃) d 8.01(d, 1H), 7.02(s, 2H), 6.13(s, 1H), 3.85(s,3H), 3.48(m, 1H), 2.58(m, 2H), 2.37(m, 1H), 2.09(s, 3H), 2.07(s, 6H),1.82(m, 1H) 1.42(m, 2H), 1.25(m 4H1, 0.97(t, t, 3H), 0.86(m, 6H) ppm

EXAMPLE 2322-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-4-(1-propylaminomethyl-propylamino)-nicotinicacid methyl ester

[0529] 1H NMR(CDCl₃) d 8.09(d, 1H), 7.02(s, 2H), 6.19(s, 1H), 3.86(s,3H), 3.60(m, 1H), 2.76(m, 2H), 2.61(t, 2H), 2.10(s, 3H), 2.07(s, 6H),1.61(m, 6H), 0.97(t,3H), 0.91(t, 3H)ppm

EXAMPLE 2332-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-{[(furan-2-ylmethyl)-amino]-methyl}-propylamino)-6-methyl-nicotinicacid methyl ester

[0530] 1H NMR(CDCl₃) d 8.09(d, 1H), 7.37(s, 1H), 7.02(s,2H), 6.31(dd,2H), 6.17(s, 1H), 3.87(s, 3H), 3.84(s, 2H), 3.58(m, 1H), 2.75(m, 2H),2.09(s,3H), 2.07(s, 6H), 1.70(m, 1H), 1.58(m, 1H), 0.95(t, 3H)ppm

EXAMPLE 2342-(4-Chloro-2,6-dimethyl-phenoxy)-4-{1-[(2-methoxy-ethylamino)-methyl]-propylamino}-6-methyl-nicotinicacid methyl ester

[0531] 1H NMR(CDCl₃) d 8.10(d, 1H), 7.02(s, 2H), 6.19(s, 1H), 3.87(s,3H), 3.61(m, 1H), 3.51(m, 2H), 3.34(s, 3H), 2.84(m, 2H), 2.79(m, 2H),2.10(s, 3H), 2.07(s, 6H), 1.71(m, 1H), 1.57(m, 1H), 0.98(t, 3H)ppm

EXAMPLE 2352-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-dimethylaminomethyl-propylamino)-6-methyl-nicotinicacid methyl ester

[0532] 1HNMR(CDCl₃) 8.14(d, 1H), 7.02(s, 2H), 6.10(s, 1H), 3.86(s, 3H),3.53(m, 1H), 2.44(m, 2H), 2.29(s, 6H), 2.10(s, 3H), 2.07(s, 6H), 1.78(m,1H), 1.56(m, 1H), 0.97(t, 3H)ppm

EXAMPLE 2364-[(2-Butylamino-ethyl)-ethyl-amino]-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-nicotinicacid methyl ester

[0533] 1HNMR(CDCl₃) 7.00(s, 2H), 6.31 (s, 1H), 3.88(s, 3H), 3.41(t, 2H),3.26(m, 2H), 2.82(t, 2H), 2.65(t, 2H), 2.15(s, 3H), 2.05(s, 6H), 1.51(m,2H), 1.34(m, 2H), 1.12(t, 3H), 0.89(t, 3H)ppm

EXAMPLE 2372-(4-Chloro-2,6-dimethyl-phenoxy)-4-(S,S)-(1-ethyl-2-methylamino-propylamino)-6-methyl-nicotinicacid methyl ester

[0534] The title compound was prepared by a reductive amination as shownabove starting with2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-oxo-propylamino)-6-methyl-nicotinicacid methyl ester and methyl amine. APCl M+1 [420.2], 1H NMR(CDCl₃)

EXAMPLE 2382-(4-Chloro-2,6-dimethyl-phenoxy)-4-(S,R)-(1-ethyl-2-methylamino-propylamino)-6-methyl-nicotinicacid methyl ester

[0535] The title compound was prepared by a reductive amination as shownabove starting with2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-oxo-propylamino)-6-methyl-nicotinicacid methyl ester and methyl amine. APCl M+1 [420.2], 1H NMR(CDCl₃)

EXAMPLE 2392-(4-Methoxy-2,6-dimethyl-phenoxy)-6-methyl-4-(1-methylsulfanylmethyl-propylamino)-nicotinicacid methyl ester

[0536] A mixture of2-(4-methoxy-2,6-dimethyl-phenoxy)-4-(1-methanesulfonyloxymethyl-propylamino)-6-methyl-nicotinicacid methyl ester and sodium iodide in acetonitrile was stirred at rtfor 2 hr, then NaSMe was added. The mixture was heated at 60° C.overnight. DMSO and additional NaSMe were added and heated foradditional hours until all starting material was consumed. The mixturewas quenched with water, extracted with ethyl acetate. The organic layerwas separated, dried, concentrated, and purified to give the titlecompound.

[0537] 1HNMR(CDCl₃) 8.23(d, 1H), 6.59(s, 2H), 6.10(s, 1H), 3.87(s, 3H),3.78(s, 3H), 3.60(m, 1H), 2.75(m, 1H), 2.65(m, 1H), 2.14(s, 3H), 2.08(m,9H), 1.85(m, 1H), 1.66(m, 1H), 1.00(t, 3H)ppm

[0538] The following compounds (Examples 240-243) were prepared by themethod similar to that described in Example 239 starting with anappropriate2-(substituted-phenoxy)-4-(1-methanesulfonyloxymethyl-propylamino)-3,6-substituted-pyridinewith an appropriate nucleophile:

EXAMPLE 2402-(4-Methoxy-2,6-dimethyl-phenoxy)-6-methyl-4-(1-[1,2,4]triazol-1-ylmethyl-propylamino)-nicotinicacid methyl ester

[0539] 1H(CDCl₃) 8.23(d, 1H), 8.02(s, 1H), 7.95( s, 2H), 5.92(s, 1H),6.59(s, 2H), 5.93(s, 1H), 4.31(m, 1H), 4.22(m, 1H), 3.93(m, 1H), 3.87(s,3H), 3.77(s, 3H), 2.10(s, 3H), 2.07(s, 6H), 1.70(m, 1H), 1.59(m, 1H),1.04(t, 3H)ppm

EXAMPLE 2412-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-4-(1-methylsulfanylmethyl-propylamino)-nicotinicacid methyl ester

[0540] 1HNMR(CDCl₃) 8.27(d, 1H), 7.02(s, 2H), 6.12(s, 1H), 3.87(s, 3H),3.61(m, 1H), 2.70(m, 2H), 2.17(s, 3H), 2.14(s, 3H), 2.08(s, 6H), 1.85(m,2H), 1.00(t, 3H)ppm

EXAMPLE 242 2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(2-ethyl-aziridin-1-yl)-6-methyl-nicotinic acid methyl ester

[0541] 7.02(s,2H), 6.38(s,1H), 3.95(s,3H), 2.27(m,1H), 2.18(s,3H),2.15(m,2H), 2.06(s,6H), 1.75(m,1H), 1.63(m,1H), 1.06(t,3H)ppm.

EXAMPLE 2432-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-4-[1-(3H-[1,2,3]triazol-4-ylsulfanylmethyl)-propylamino]-nicotinicacid methyl ester

[0542] 1HNMR(CDCl₃) 8.32(d, 1H), 7.54(s, 1H), 6.95(s, 2H), 6.13(s, 1H),3.87(s, 3H), 3.67(m, 1H), 3.20(m, 1H), 3.05(m, 1H), 2.05(m, 9H), 1.99(m,1H), 1.67(m, 1H), 1.01(t, 3H)ppm

EXAMPLE 2442-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-3-methanesulfonyl-propylamino)-6-methyl-nicotinicacid methyl ester

[0543] The title compound was prepared by oxidation of2-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-3-methylsulfanyl-propylamino)-6-methyl-nicotinicacid methyl ester with m-chloroperbenzoic acid in methylene chloride atrt. for 2 hrs. IH NMR(CDCl₃) d 8.32(d,1H), 7.04(s,2H), 6.23(s,1H),3.88(s,3H), 3.7-3.9(m,3H), 3.1-3.3(m,2H), 2.95(s,3H), 2.0-2.4(m,2H).2.13(s,3H), 2.07(s,6H) ppm.

[0544] The following compounds (Examples 245-248) were prepared by themethod analogous to that described in Example 188:

EXAMPLE 2452-(4-Ethoxy-2,6-dimethyl-phenoxy)-6-methyl-4-(tetrahydro-furan-3-ylamino)-nicotinicacid methyl ester

[0545] 1H NMR(CDCl₃) d 8.35(d, 1H), 6.59(s, 2H), 6.08(s, 1H), 4.03(m,1H), 4.01(m, 4H), 3.99(m, 1H), 3.92(s, 3H), 3.89(m, 1H), 2.34(m, 1H),2.25(m, 3H), 2.08(s, 6H), 1.39(t, 3H)ppm

EXAMPLE 2462-[4-(2-Methoxy-ethoxy)-2,6-dimethyl-phenoxy]-6-methyl-4-(tetrahydro-furan-3-ylamino)-nicotinicacid methyl ester

[0546] 1H NMR(CDCl₃) d 8.30(d, 1H), 6.62(s, 2H), 6.07(s, 1H), 4.10(m,3H), 4.02(m, 2H), 3.98(m, 1H), 3.85(s, 2H), 3.75(m, 3H), 3.45(s, 3H),2.32(m, 1H), 2.19(s, 3H), 2.07(s, 6H)ppm

EXAMPLE 2472-(2,6-Dimethyl-4-trifluoromethoxy-phenoxy)-6-methyl-4-(tetrahydro-furan-3-ylamino)-nicotinicacid methyl ester

[0547] 1H NMR(CDCl₃) d 8.29 (d, 1H, J=6 Hz), 6.91 (s, 2H), 6.06 (s, 1H),4.11-4.33 (m, 1H), 3.97-4.05 (m, 2H), 3.89-3.93 (m, 1H), 3.87 (s, 3H),3.72-3.76 (m, 1H), 2.31-2.35 (m, 1H), 2.14 (s, 3H), 2.10 (s, 6H),1.94-1.96 (m, 1H)ppm. APCl+m/z=441.2 (M+1)

EXAMPLE 2482-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-4-(R)-(tetrahydro-furan-3-ylamino)-nicotinicacid methyl ester

[0548] APCl+m/z=391.3 (M+1)

EXAMPLE 2492-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-3-iodo-propylamino)-6-methyl-nicotinicacid methyl ester

[0549] APCl [M+1]518.9, 520.9

EXAMPLE 2502-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-3-methanesulfinyl-propylamino)-6-methyl-nicotinicacid methyl ester

[0550] 1H NMR(CDCl₃) d 8.31(d,1H), 7.03(s,2H), 6.24(s,0.5H),6.28(s,0.5H), 3.87(s,3H), 3.65-3.9(m,3H), 2.7-3.0(m,2H), 2.60(s,3H),2.0-2.4(m,2H), 2.14(s,3H), 2.07(s,6H) ppm.

EXAMPLE 2512-(4-Cyclopropyloxy-2,6-dimethyl-phenoxy)-6-methyl-4-(tetrahydro-furan-3-ylamino)-nicotinicacid methyl ester

[0551] 1H NMR (CDCl₃) d 8.32(d, 1H), 6.73(s, 2H), 6.07(s, 1H),4.13(m,1H), 4.01(m, 4H), 3.98(m, 1H), 3.85(s, 3H), 3.72(m, 2H), 2.22(s,3H), 2.09(s, 6H0, 0.87(m,2H), 0.75(m, 4H)ppm

EXAMPLE 2522-(4-Chloro-2,6-dimethoxy-phenoxy)-6-methyl-4-(tetrahydro-furan-3-ylamino)-nicotinicacid methyl ester EXAMPLE 2534-sec-Butylamino-6-methyl-2-(2,4,6-trimethyl-pyridin-3-yloxy)-nicotinicacid methyl ester

[0552] 1H NMR(CDCl₃) 8.08(d, 1H), 686(s, 1H), 6.09(s, 1H), 3.86(s, 3H),3.48(m, 1H), 2.49(s, 3H), 2.31 (s, 3H), 2.08(s, 6H), 1.63(m, 2H), 1.21(d, 3H), 0.98(t, 3H)ppm

EXAMPLE 2542-(4-Chloro-2,6-dimethyl-phenoxy)-{ethyl-[2-(ethyl-methyl-amino)-ethyl}-amino]-6-methyl-nicotinicacid methyl ester EXAMPLE 2552-(4-Chloro-2,6-dimethyl-phenoxy)-4-[ethyl(2-propylamino-ethyl)-amino]-6-methyl-nicotinicacid methyl ester EXAMPLE 2564-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-pyridin-3-yloxy)-nicotinicacid methyl ester

[0553] 1H NMR(CDCl₃) 8.09(d, 1H), 6.86(s, 1H), 6.08(s, 1H), 3.86(s, 3H),3.33(m, 1H), 2.49(s, 3H), 2.31(s, 3H), 2.07(s, 6H), 1.63(m, 4H), 0.94(t,6H)ppm

[0554] 1H NMR(CDCl₃) d 8.39 d, 1H, J=6 Hz), 6.63 (s, 2H), 6.06 (s, 1H),4.08-4.15 (m, 1H), 3.95-4.05 (m, 2H), 3.88-3.92 (m, 1H), 3.86 (s, 3H),3.73 (s, 6H), 3.67-3.73 (m, 1H), 2.26-2.35 (m, 1H), 2.14 (s, 3H),1.89-1.96 (m, 1H) ppm.

[0555] The following Examples 257-287 relate to other compounds offormula I of the invention, wherein R₄ is —C(O)NR₂₄R₂₅:

[0556] The following compounds (Examples 257-280) were prepared by amethod analogous to that in Example 113 starting with the correspondingnicotinic acid or pyrimidine-5-carboxylic derivative and quenching withan appropriate nucleophile; these compounds can also be prepared bycoupling of 2-(substituted-phenoxy)-6-methyl-4-chloro-nicotinamideand/or -N-substituted-nicotinamide with an appropriate amine in NMP at130-160° C.:

EXAMPLE 2572-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-4-(tetrahydro-furan-3-ylamino)-nicotinamide

[0557] 1H NMR(CDCl₃) d 9.99(d,1H), 7.85(brs, 1H), 7.07(s,2H),6.13(s,1H), 5.62(brs,1H), 3.7-4.2(m,5H), 2.95(d,3H), 2.31 (m,1H),2.20(s,3H), 2.09(s,6H), 2.01 (m,1H) ppm.

EXAMPLE 2582-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-3-methylsulfanyl-propylamino)-6-methyl-nicotinamide

[0558] 1H NMR(CDCl₃) d 9.78(d,1H), 7.97(brs, 1H), 7.06(s,2H),6.32(s,1H), 5.77(brs,1H), 3.6-3.9(m,3H), 2.5-2.7(m,2H), 2.0-2.2(m, 12H),1 .8-2.0(m,2H)ppm.

EXAMPLE 2592-(4-Chloro-2,6-dimethyl-phenoxy)-6,N-dimethyl-4-(S)-(tetrahydro-furan-3-ylamino)-nicotinamide

[0559] 1H NMR(CDCl₃) d 10.00(d,1H), 8.05(brs, 1H), 7.06(s,2H),6.10(s,1H), 4.09(m,1H), 3.96-4.05(m,3H), 3.73(m,1H), 2.95(d,3H),2.31(m,1H), 2.12(s,3H), 2.06(s,6H), 1.96(m,1H) ppm.

EXAMPLE 2602-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6,N-dimethyl-nicotinamide

[0560] 1H NMR(CDCl₃) d 9.78(d,1H), 8.10(brs, 1H), 7.06(s,2H),6.13(s,1H), 3.32(m,1H), 2.96(d,3H), 2.09(s,3H), 2.08(s,6H), 1.65(m,4H),0.96(t,6H)ppm.

EXAMPLE 261 4-sec-Butylamino-2-(4-chloro-2,6-dimethyl-phenoxy)-6,N-dimethyl-nicotinamide

[0561] 1H NMR(CDCl₃) d 9.78(d,1H), 8.04(brs, 1H), 7.07(s,2H),6.14(s,1H), 3.46(m,1H), 2.95(d,3H), 2.15(s,3H), 2.09(s,6H),1.1.58(m,2H), 1.23(d,3H), 0.99(t,6H)ppm.

EXAMPLE 2624-(1-Ethyl-propylamino)-2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-nicotinamide

[0562] Mp=184° C. Found: C, 67.68, H, 8.12, N, 10.81; Cale: C, 67.90, H,7.87, N, 11.31. 1H(CDCl₃) 9.67(d, 1H), 8.06(m, 1H) 6.61 (s, 2H), 6.11(s, 1H), 5.48(s, 1H), 3.79(s, 3H), 3.32(m, 1H), 2.09(s, 9H), 1.61 (s,4H), 0.95(t, 6H)ppm

EXAMPLE 2634-(1-Ethyl-propylamino)-2-(4-methoxy-2,6-dimethyl-phenoxy)-6,N-dimethyl-nicotinamide

[0563] 1H(CDCl₃) 9.78(d, 1H), 8.22(m, 1H), 6.60(s, 2H), 6.10(s, 1H),3.78(s, 3H), 3.25(m, 1H), 2.93(d, 3H), 2.07(s, 9H), 1.61(m, 4H), 0.95(t.6H)ppm

EXAMPLE 2642-(4-Methoxy-2,6-dimethyl-phenoxy)-4-(1-methoxymethyl-propylamino)-6-methyl-nicotinamide

[0564] 1HNMR(CDCl₃) 9.80(d, 1H), 8.04(s, 1H), 6.61(s, 2H), 6.18(s, 1H),5.62(s, 1H), 3.78(s, 3H), 3.51(m, 2H), 3.39(s, 3H), 2.09(s, 3H), 2.08(s,6H), 1.79(m, 1H), 1.59(m, 1H), 0.99(t, 3H)ppm

EXAMPLE 2652-(4-Methoxy-2,6-dimethyl-phenoxy)-4-(1-methoxymethyl-propylamino)-6,N-dimethyl-nicotinamide

[0565] 1HNMR(CDCl₃) 9.92(d, 1H), 8.22(s, 1H), 6.62(s, 2H), 6.19(s, 1H),3.79(s, 3H), 3.5(m,, 2H), 3.38(s, 3H), 2.94(d, 3H), 2.12(s, 3H), 2.08(s,6H), 1.80(m, 1H), 1.61(m, 1H), 1.00(t, 3H)ppm

EXAMPLE 2664-(1-Hydroxymethyl-propylamino)-2-(4-methoxy-2,6-dimethyl-phenoxy)-6,N-dimethyl-nicotinamide

[0566] 1HNMR(CDCl₃) 9.79(d, 1H), 8.28(d, 1H), 6.62(s, 2H), 6.24(s, 1H),3.79(s, 3H), 3.70(m, 2H), 3.54(m, 1H), 2.94(d, 3H), 2.08(s, 6H), 1.62(m,2H), 1.01 (t, 3H)ppm

EXAMPLE 2674-sec-Butylamino-2-(4-methoxy-2,6-dimethyl-phenoxy)-6,N-dimethyl-nicotinamide

[0567] 1HNMR(CDCl₃) 9.76(d, 1H), 8.26(d, 1H), 6.61(s, 2H), 6.12(s, 1H),3.79(s, 3H), 3.46(m, 1H), 2.94(d, 3H), 2.09(s, 3H), 2.07(s, 6H), 1.64(m,2H), 1.24(m, 3H), 0.98(t, 3H)ppm

EXAMPLE 2682-(4-Chloro-2,6-dimethyl-phenoxy)-4-(S)-(1-methoxymethyl-propylamino)-6,N-dimethyl-nicotinamide

[0568] Anal. For C₂₁H₂₈ClN₃O₃ calc. C, 62.14% H, 6.95%, N, 10.35%; foundC, 62.12%, H, 6.95%, N, 10.42%.

EXAMPLE 2692-(4-Chloro-2,6-dimethyl-phenoxy)-4-(S)-(1-methoxymethyl-propylamino)-6-methyl-nicotinamide

[0569] Anal. For C₂₀H₂₆ClN₃O₃ calc. C, 61.30% H, 6.69%, N, 10.725%;found C, 60.97%, H, 6.53%, N, 10.47%.

EXAMPLE 2702-(4-Chloro-2,6-dimethyl-phenoxy)-6,N-dimethyl-4-(1-methylsulfanylmethyl-propylamino)-nicotinamide

[0570] 1HNMR(CDCl₃) 9.97(d, 1H), 8.1(brs, 1H), 7.06(s, 2H), 6.16(s, 1H),3.56(m, 1H), 2.96(s, 3H), 2.6-2.8(m,2H), 2.17(s, 3H), 2.11(s,3H),2.08(s, 6H), 1.6-1.9(m, 2H), 1.24(m, 3H), 1.00(t, 3H)ppm

EXAMPLE 2712-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-4-(1-methylsulfanylmethyl-propylamino)-nicotinamide

[0571] 1HNMR(CDCl₃) 9.89(d, 1H), 7.9(brs, 1H), 7.06(s, 2H), 6.16(s, 1H),3.56(m,1H), 2.6-2.8(m,2H), 2.17(s, 3H), 2.11(s,3H), 2.07(s, 6H),1.6-1.9(m, 2H), 1.24(m, 3H), 0.99(t, 3H)ppm

EXAMPLE 2722-(4-Chloro-2-methoxy-phenoxy)-4-(1-ethyl-propylamino)-6,N-dimethyl-nicotinamide

[0572] 1H NMR(CDCl₃) d 9.40 (d, 1H, J+8 Hz), 8.10 (br s, 1H), 7.17 (d,1H, J=9 Hz), 6.94-6.96 (m, 2H), 6.14 (s, 1H), 3.79 (s, 3H), 3.27-3.31(m, 1H), 2.93 (d, J=5 Hz) 2.14 (s, 3H), 1.51-1.66 (m, 4H), 0.95 (t, 6H,J=7 Hz) ppm.. Cl+m/z=392.2 (M+1), 394.2 (M+3)

EXAMPLE 2732-(4-Chloro-2-methoxy-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-nicotinamide

[0573] 1H NMR(CDCl₃) d 9.40 (d, 1H), 7.92 (brs, 1H), 7.17 (d, 1H, J=9Hz), 6.94-6.96 (m, 2H), 6.15 (s, 1H), 5.48 (br s, 1H), 3.77 (s, 3H),3.28-3.36 (m, 1H), 2.16 (s, 3H), 1.52-1.66 (m, 4H), 0.94 (t, 6H, J=7 Hz)ppm.

[0574] APCl+m/z=378.1 (M+1), 380.1 (M+3)

EXAMPLE 2742-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-cyclopropylmethoxymethyl-propylamno)6-methyl-nicotinamide

[0575] 1H NMR(CDCl₃) d 9.70 (d, 1H), 7.90 (brs, 1H), 7.05 (s, 1H), 6.22(s, 1H), 5.6 (br s, 1H), 3.57 (m, 2H), 3.43(m,1H), 3.33(d,3H),2.09(s,6H), 2.07 (s, 3H), 1.5-1.9 (m, 2H), 0.9-1.0(m,4H), 0.53(m,2H),0.50(m,2H) ppm.

EXAMPLE 2752-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethoxymethyl-propylamino)-6-methyl-nicotinamide

[0576] 1H NMR(CDCl₃) d 9.75 (d, 1H), 7.90 (brs, 1H), 7.05 (s, 1H), 6.21(s, 1H), 5.6 (br s, 1H), 3.3-3.6(m,4H), 2.08(s,6H), 2.07 (s, 3H),1.5-1.9 (m, 2H), 1 .20(t,3H), 1.00(t,3H) ppm.

EXAMPLE 2762-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethoxymethyl-propylamino)-N-ethyl-6-methyl-nicotinamide

[0577] 1H NMR(CDCl₃) d 9.78 (d, 1H), 8.09 (t, 1H), 7.06 (s, 1H), 6.22(s, 1H), 5.6 (br s, 1H), 3.3-3.6(m,6H), 2.09(s,3H), 2.08 (s, 6H),1.5-1.9 (m, 2H), 1.20-1.4(m,6H), 1.00(t,3H) ppm.

EXAMPLE 2772-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethoxymethyl-propylamino)-6,N-dimethyl-nicotinamide

[0578] 1H NMR(CDCl₃) d 9.8(d, 1H), 8.1 (brs, 1H), 7.06 (s, 1H), 6.22 (s,1H), 3.54(m,3H), 3.38(m,1H), 2.94(d,3H), 2.08(s,6H), 2.07 (s, 3H),1.83(m,1H), 1.60(m,1H), 1.20(t,3H), 1.00(t,3H) ppm.

EXAMPLE 2782-(4-Bromo-2-methoxy-phenoxy)-4-(1-ethyl-propylamino)-6,N-dimethyl-nicotinamide

[0579] 1H NMR(CDCl₃) d 9.41 (br d, 1H), 8.08 (br s, 1H), 7.09-7.12 (m,3H), 6.15 (s, 1H), 3.79 (s, 1H), 3.28-3.33 (m, 1H), 2.93 (d, 3H, J=5Hz), 2.15 (s, 3H), 1.501-1.65 (m, 4H), 0.95 (t, 6H, J=8 Hz)

[0580] APCl+m/z=436.1 (M+1), 438.1 (M+3)

EXAMPLE 2792-(4-Bromo-2-methoxy-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-nicotinamide

[0581] 1H NMR(CDCl₃) d 9.39 (br d, 1H), 7.91 (br s, 1H), 7.09-7.11 (m,3H), 6.15 (s, 1H), 5.49 (br s, 1H), 3.77 (s, 3H), 3.29-3.34 (m, 1H),2.15 (s, 3H), 1.51-1.67 (m, 4H), 0.94 (t, 6H, J=7 Hz) ppm.

[0582] APCl+m/z=422.1 (M+1), 424.1 (M+3)

EXAMPLE 2802-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-chloromethyl-propylamino)-6-methyl-nicotinamide

[0583] 1H NMR(CDCl₃) d 9.93(d,1H), 7.9(brs,1H), 7.06(s,2H), 6.16(s,1H),5.6(brs,1H), 3.4-3.7(m,3H), 2.1(s,3H), 2.08(s,6H), 1.9(m,1H),1.65(m,1H), 1.03(t,3H) ppm.

EXAMPLE 2812-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-formyl-propylamino)-6-methyl-nicotinamide

[0584] A mixture of2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-methyl-nicotinamideand Dess-Martin reagent in methylene chloride/DMSO was stirred at rt for4 hr. The title compound was isolated after standard work-up and silicagel Biotage purification. 1H NMR(CDCl₃) d 9.52(s,1H), 8.00(brs,1H),7.06(s,22H), 5.99(s,1H), 5.8(brs,1H), 3.85(m,1H), 2.09(s,3H),2.08(s,6H), 1.8-2.2(m,2H), 1.08(t,3H) ppm.

EXAMPLE 2824-(1-Formyl-propylamino)-2-(4-methoxy-2,6-dimethyl-phenoxy)-6,N-dimethyl-nicotinamide

[0585] The title compound was prepared by a method analogous to thatdescribed in Example 281.

[0586] 1HNMR(CDCl₃) 9.51(s, 1H), 8.32(m, 1H), 6.62(s, 2H), 5.97(s, 1H),3.81(m, 1H), 3.79(s, 3H), 2.96(m, 3H), 2.08(m, 9H), 1.89(m, 2H), 1.09(t,3H)ppm

EXAMPLE 2832-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-hydroxy-propylamino)-6-methyl-nicotinamide

[0587] To a solution of MeMgBr in dry THF was added a solution of2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-formyl-propylamino)-6-methyl-nicotinamidein dry THF at −78° C. The mixture was stirred at −78° C. for 2 hr, thenquenched with dilute acid. After standard extraction and purification,the title compound was obtained. 1H NMR(CDCl₃) d 9.8(d,1H),7.9(nbrs,1H)., 7.05(s,2H), 6.27(s,0.5H), 6.24(s,0.5H), 5.6(brs,1H),3.91(m,0.5H), 3.89(m,0.5H), 3.51(m,0.5H), 3.3(m,0.5H), 2.09(s,9H),1.5-1.8(m,2H), 1.26(d,3H), 0.98(t,3H) ppm.

EXAMPLE 284 4-(1-Ethyl-2-methoxy-propylamino)-2-(4-methoxy-2,6-dimethyl-phenoxy)-6,N-dimethyl-nicotinamide

[0588] 1HNMR(CDCl₃) 9.87(d, 1H), 8.26(d, 1H), 6.61(s, 2H), 6.16(s, 1H),3.79(s, 3H), 3.46(m, 1H), 3.40(s, 3H), 2.94(d, 3H), 2.08(s, 9H), 1.76(m,1H), 1.65(m, 1H), 1.25(m, 1H), 1.17(d, 3H), 0.98(t, 3H)ppm mp=122.6° C.

EXAMPLE 2852-(4-Bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-nicotinamide

[0589] To a mixture of2-chloro-4-(1-ethyl-propylamino)-6-methyl-nicotinamide and2,6-dimethyl-4-bromo-phenol in NMP was added t-BuOK. The resultingmixture was heated in a 160° C. oil bath overnight. The mixture wasquenched with water and extracted with ethyl acetate. The organic layerwas separated, dried and concentrated, then purified through silica gelBiotage to give the title compound. 1H NMR(CDCl₃) d 9.69(d,1H),7.89(brs,1H), 7.20(s,2H), 6.13(s,1H), 5.5(brs,1H), 3.3(m,1H),2.10(s,3H), 2.09(s,6H), 1.6(m,4H), 0.95(t,6H) ppm.

EXAMPLE 2864-(1-Ethyl-propylamino)-6,N-dimethyl-2-(2,4,6-trimethyl-pyridin-3-yloxy)-nicotinamide

[0590] 1H(CDCl₃) 9.74(d, 1H), 8.08(s, 1H), 6.90(s, 1H), 6.12(s, 1H),3.31(m,1H), 2.96(d, 3H), 2.51 (s, 3H), 2.30(s, 3H), 2.08(s, 3H), 2.05(s,3H), 1.60(m, 4H), 0.95(t, 3H)ppm

EXAMPLE 2874-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-pyridin-3-yloxy)-nicotinamide

[0591] MP=164.3° C. 1H NMR (CDCl₃) 9.65(d, 1H), 7.8(s, 1H), 6.91(s, 1H),6.14(s, 1H), 5.50(s, 1H), 3.32(m, 1H), 2.53(s, 3H), 2.34(s, 3H), 2.17(s,3H), 2.10(s, 3H), 1.60(m, 4H), 0.95(t, 6H)ppm

[0592] The following Examples 288-294 relate to other compounds offormula I of the invention, wherein R₄ is —C(O)R₂₄, for example—C(O)CH₃:

EXAMPLE 2881-[4-(1-Ethyl-propylamino)-2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-pyridin-3-yl]-ethanone

[0593] 1HNMR(CDCl₃) 9.74(d, 1H), 6.61(s, 2H), 6.10(s, 1H), 3.79(s, 3H),3.39(m, 1H), 2.73(s, 3H), 2.10(s, 9H), 1.62(m, 4H), 0.94(t, 6H)ppm

EXAMPLE 289N-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-N-(2-pyrrolidin-1-yl-ethyl)-acetamide

[0594] 1H NMR(CDCl₃) d 6.89 (s, 2H), 6.60 (s, 1H), 4.00-4.07 (m, 1H),3.53-3.59 (m, 1H), 2.59-2.72 (m, 2H), 2.52 (br s, 4H), 2.30 (s, 3H),2.24 (s, 3H), 2.22 (s, 3H), 2.04 (s, 6H), 1.84 (S, 3H), 1.74 (br s, 4H)ppm.

EXAMPLE 290N-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-N-(2-pyrrolidin-1-yl-ethyl-isobutyramide

[0595] 1H NMR(CDCl₃) d 6.89 (s, 2H), 6.56 (s, 1H), 4.09-4.17 (m, 1H),3.38-3.48 (m, 1H), 2.65-2.77 (m, 2H), 2.61 (br s, 4H), 2.33-2.40 (m, 1H), 2.30 (s, 3H), 2.24 (s, 3H), 2.20 (s, 3H), 2.05 (s, 6H), 1.77 (br s,4H), 1.04 (t, 6H, J=7 Hz) ppm.

EXAMPLE 291N-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-N-(2-pyrrolidin-1-yl-ethyl)-malonamicacid ethyl ester

[0596] 1H NMR(CDCl₃) d 6.89 (s, 2H), 6.63 (s, 1H), 4.11-4.17 (m, 3H),3.44-3.56 (m, 1H), 3.15 (s, 2H), 2.72 (br s, 2H), 2.57 (br s, 4H), 2.30(s, 3H), 2.24 (s, 3H), 2.23 (s, 3H), 2.04 (s, 6H), 1.77 (br s, 4H), 1.24(t, 3H, J=7 Hz)

EXAMPLE 2922-(4-Chloro-2,6-dimethyl-phenoxy)-4-cyclopentylamino-6-methyl-pyridine-3-carbaldehyde

[0597] 1H NMR(CDCl₃) d 9.42(d,1H), 7.05(s,2H), 6.09(s,1H), 4.18(brs,1H),4.06(m,2H), 3.95(m,1H), 3.77(m,1H), 2.35(m,1H), 2.17(s,3H), 2.09(s,6H),1.98(m,1H) ppm.

EXAMPLE 2934-(1-Ethyl-propylamino)-2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-pyridine-3-carbaldehyde

[0598] 1HNMR(CDCl₃) 9.26(d, 1H), 6.60(s, 2H), 6.10(s, 1H), 3.78(s, 3H),3.40(m, 1H), 2.14(s, 3H), 2.11 (s, 6H), 1.66(m, 4H), 0.96(t, 6H)ppm

EXAMPLE 2941-[2-(4-Chloro-2-methoxy-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-pyridin-3-yl]-ethanone

[0599] 1H NMR(CDCl₃) d 9.59 (br d, 1H), 6.93-7.02 (m, 3H), 6.14 (s, 1H),3.78 (s, 3H), 3.33-3.38 (m, 1H), 2.69 (s, 3H), 2.14 (s, 3H), 1.49-1.67(m, 4H), 0.94 (t, 6H, J=7 Hz) ppm.

[0600] The following Examples 295-329 relate to other compounds offormula I of the invention, wherein R₄ is methyl:

EXAMPLE 295sec-Butyl-[2-(2,6-dimethyl-4-trifluoromethoxy-phenoxy)-3,6-dimethyl-pyridin-4-yl]-amine

[0601] 1H NMR(CDCl₃) d 6.90 (s, 2H), 6.09 (s, 1H), 3.78 (d, 1H, J=8Hz),3.45-3.52 (m, 1H), 2.15 (s, 3H), 2.10 (s, 9H), 1.51-1.67 (m, 2H), 1.23(d, 3H, J=8Hz), 0.98 (t, 3H, J=7 Hz) ppm.

EXAMPLE 296[2-(2,6-Dimethyl-4-trifluoromethoxy-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-amine

[0602] 1H NMR(CDCl₃) d 6.91 (s, 2H), 6.08 (s, 1H), 3.74 (d, 1H, J=8Hz),3.31-3.34 (m, 1H), 2.15 (s, 3H), 2.11 (s, 6H), 2.08 (s, 3H), 1.49-1.68(m, 4H), 0.96 (t, 6H, J=8 Hz) ppm.

EXAMPLE 297[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(2-pyrrolidin-1-yl-ethyl)-(2,2,2-trifluoro-ethyl)-amine

[0603] 1H NMR(CDCl₃) d 6.87 (s, 2H), 6.55 (s, 1H), 3.78 (q, 2H, J=9 Hz),3.60-3.72 (m, 2H), 2.82-2.98 (m, 6H), 2.29 (s, 3H), 2.26 (s, 3H), 2.20(s, 3H), 2.03 (s, 6H), 1.96 (br s, 4H) ppm.

[0604] The following compounds (Examples 298 and 299) were preparedstarting with an appropriate2-(substituted-phenoxy)-4-(1-methanesulfonyloxymethyl-propylamino)-3,6-substituted-pyridinewith an appropriate amine:

EXAMPLE 298N2-[2-(4-Chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-N1-cyclopropylmethyl-butane-1,2-diamine

[0605] 1H NMR(CDCl₃) d 7.01(s, 2H), 6.17(s, 1H), 4.40(d, 1H), 3.82(m,1H), 3.05(m, 2H), 2.69(m, 2H), 2.20(s, 3H), 2.12(s, 3H), 2.04(s,6H),1.70(m, 2H), 0.98(t, 3H), 0.96( m, 4H) ppm

EXAMPLE 299N-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-N-ethyl-N′,N′-dimethyl-ethane-1,2-diamine

[0606] 1H NMR(CDCl₃) d 6.86(s, 2H), 6.43 (s, 1H), 3.26 (AB quartet, 2H),3.12 (q, 2H, J=7 Hz), 2.51 (AB quartet, 2H), 2.34 (s, 6H), 2.29 (s, 3H),2.23 (s, 3H), 2.18 (s, 3H), 2.05 (s, 6H), 1.09 (t, 3H, J=7 Hz) ppm.

EXAMPLE 300N-2-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-N-1-methyl-butane-1,2-diamine

[0607] 1HNMR(CDCl₃) 6.85(s, 2H), 6.12(s, 1H), 4012(d, 1H), 3.56(m, 1H),2.79(m, 2H), 2.47(s, 3H), 2.28(s, 3H), 2.14(d, 6H), 2.06(s, 6H), 1.62(m,2H), 0.97(t, 3H)ppm

EXAMPLE 301N-2-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-N-1-ethyl-butane-1,2-diamine

[0608] 1H NMR(CDCl₃) d 7.80(s, 1H), 6.85(s, 2H), 6.12(s, 1H), 4.22(d,1H), 3.57(m, 1H), 2.82(m, 2H), 2.72(q, 2H), 2.28(s, 3H), 2.13(s, 6H),2.06(s, 6H), 1.63(m, 2H), 1.16(t, 3H), 0.97(t, 3H)ppm

EXAMPLE 302 N2-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-N 1-ethyl-N1-methyl-butane-1,2-diamine

[0609] 1H NMR (CDCl₃) d 6.85(s ,2H), 6.06(s, 1H), 4.58(m, 1H), 3.39(m,1H), 2.49(m, 4H), 2.28(s, 6H), 2.14(s, 6H), 2.06(s, 6H), 1.66(m, 2H),1.08(m, 3H), 0.96(t, 3H)ppm

EXAMPLE 303N-1-Butyl-N-2-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-butane-1,2-diamine

[0610] 1H NMR(CDCl₃) d 6.85(s, 2H), 6.11(s, 1H), 4.21(d, 1H), 3.51(q,1H), 2.79(m, 2H),2.65(t, 2H), 2.28(s, 3H), 2.14(s, 6H), 2.06(s,6H),1.62(m, 2H), 1.49(m, 2H), 1.35(m, 2H), 0.97(t, 3H), 0.91 (t, 3H)ppm

EXAMPLE 304N-1-Cyclopropylmethyl-N-2-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-N1-propyl-butane-1,2-diamine

[0611] 1H NMR (CDCl₃) d 6.85(s, 2H), 6.06(s, 1H), 4.65(m, 1H), 3.32(m1H), 2.61(m, 4H), 2.28(s, 3H), 2.14(s,3H), 2.12(s, 2H), 2.06(s, 6H),1.71(m, 2H), 1.46(m, 2H), 0.96(t, 3H), 0.87(t, 3H)ppm

EXAMPLE 305N-2-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-N-1-propyl-butane-1,2-diamine

[0612] 1H NMR(CDCl₃) d 6.85(s, 2H), 6.11(s, 1H), 4.21(d, 1H), 3051(q,1H), 2.79(m, 2H), 2.62(m, 2H), 2.28(s, 3H), 2.13(s, 6H), 2.06(s, 6H),1.62(m, 2H), 1.54(m,2H), 0.97(t, 3H), 0.91(t, 3H)ppm

EXAMPLE 306N-2-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-N-1-(2-methoxy-ethyl)-butane-1,2-diamine

[0613] 1H NMR (CDCl₃) d 6.85(s, 2H), 6.11(s, 1H), 4.18(d, 1H), 3.51(m,3H),. 3.35(s, 2H),, 2.82(m, 4H), 2.28(s, 3H), 2.14(s, 6H), 2.06(s, 6H),1.62(m, 2H), 0.97(t, 3H)ppm

EXAMPLE 307N-2-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-N-1-furan-2-ylmethyl-butane-1,2-diamine

[0614] 1HNMR(CDCl₃) 7.36(s, 1H), 6.85(s, 2H), 6.32(d, 1H), 6.24(d, 1H),6.09(s, 1H), 4.15(d, 1H), 3.84(d, 2H), 3.58(m 1H), 2.79(m, 2H), 2.28(s,3H), 2.13(d, 6H), 2.05(s, 6H), 1.62(m, 2H), 0.95(t, 3H)ppm

EXAMPLE 308N-1-Cyclopropylmethyl-N-2-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-butane-1,2-diamine

[0615] 1HNMR(CDCl₃) 6.85(s, 2H), 6.14(s, 1H), 4.39(m, 1H), 3.70(m, 1H),3.01(m, 2H), 2.67(d, 2H), 2.28(s, 3H), 2.20(s, 3H), 2.14(s, 3H), 2.05(s,6H), 1.71(m, 2H), 0.98(t. 3H), 0.55(d, 2H), 0.21(d, 2H)ppm.

EXAMPLE 309 [3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-thiazolidin-3-ylmethyl-propyl)-amine

[0616] 1HNMR(CDCl₃) 6.85(s, 2H), 6.07(s, 1H), 4.21(d, 1H), 4.06(d, 2H),3.41(m, 1H), 3.07(m, 2H), 2.89(m, 2H), 2.52(m, 2H), 2.28(s, 3H), 2.15(d,6H), 2.06(s, 6H), 1.75(m, 1H), 1 .66(m, 1H0, 0.98(t, 3H)ppm

EXAMPLE 310N-2-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-butane-1,2-diamine

[0617] To a solution of(1-hydroxymethyl-propyl)-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-aminein toluene was added diphenylphosphoryl azide and1,8-diazbicyclo[3,4,0]undec-7-ene at 0° C. The resulting mixture wasstirred at rt for 30 min, then heated 75° C. overnight. The reactionmixture was quenched with water and extracted with methylene chloride.The organic layer was separated, dried, concentrated and purified bysilica gel Biotage using 1:1 methylene chloride/hexane to methylenechloride as eluent to give(1-azidomethyl-propyl)-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amine as a light yellow oil. The oil was reduced withtriphenylphospine to give the title compound. 1H NMR (CDCl₃) d 6.86(s,2H), 6.11(s, 1H), 4.02(d, 1H), 3.40(q, 1H), 2.84(m, 2H), 2.28(s, 3H),2.13(s, 6H), 2.06(s, 6H), 1.61 (m, 2H), 0.98(t, 3H)ppm

EXAMPLE 311 1-{2-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-ylamino]-butyl}-3-ethyl-urea

[0618] A mixture ofN-2-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-butane-1,2-diamineand ethyl isocyanate in dichloroethane was stirred at rt overnight.Standard work-up, and purification yielded the title compound. APCl[M+1]=399.3, 1H NMR(CDCl₃).

EXAMPLE 312N-{2-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-ylamino]-butyl}-methanesulfonamide

[0619] A mixture ofN-2-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-butane-1,2-diamineand methanesulfonyl chloride in dichloroethane was stirred at rtovernight. Standard work-up and purification yielded the title compound.APCl [M+1]=406.2, 1H NMR(CDCl₃)

EXAMPLE 313N-{2-[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yiamino]-butyl}-acetamide

[0620] A mixture ofN-2-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-butane-1,2-diamineand acetyl chloride in dichloroethane was stirred at rt overnight.Standard work-up and purification yielded the title compound. APCl[M+1]=370.3, 1H NMR(CDCl₃)

EXAMPLE 314Cyclopropylmethyl-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-propyl-amine

[0621] 1H NMR(CDCl₃) d 6.85 (s, 2H), 6.44 (s, 1H), 3.13 (AB q, 2H), 2.90(d, 2H, J=8 Hz), 2.28 (s, 3H), 2.24 (s, 3H), 2.16 (s, 3H), 2.05 (s, 6H),1.47-1.65 (m, 2H), 0.86-0.92 (m, 4H), 0.42-0.46 (m, 2H), 0.04-0.08 (m,2H)

[0622] APCl+m/z=353.3 (M+1)

EXAMPLE 315Cyclopropylmethyl-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-propyl-amine

[0623] 1H NMR(CDCl₃) d 6.85 (s, 2H), 6.44 (s, 1H), 3.13 (AB q, 2H), 2.90(d, 2H, J=8 Hz), 2.28 (s, 3H), 2.24 (s, 3H), 2.16 (s, 3H), 2.05 (s, 6H),1.47-1.65 (m, 2H), 0.86-0.92 (m, 4H), 0.42-0.46 (m, 2H), 0.04-0.08 (m,2H)

[0624] APCl+m/z=353.3 (M+1)

EXAMPLE 3163,6-Dimethyl-4-(2-methyl-aziridin-1-yl)-2-(2,4,6-trimethyl-phenoxy)-pyridine

[0625] 1H NMR(CDCI₃) d 6.86 (s, 2H), 6.29 (s, 1H), 2.31 (sa, 3H), 2.29(s, 3H), 2.19 (m, 1H), 2.15 (s, 3H), 2.10 (m, 2H), 2.04 (s, 6H), 1.44(d, 3H, J=5 Hz)

EXAMPLE 3174-(2-Methoxymethyl-pyrrolidin-1-yl)-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridine

[0626] 1H NMR(CDCl₃) d 6.86 (s, 2H), 6.34 (s, 1H), 3.99 (q, 1H, J=4Hz),3.67 (m, 1H), 3.49 (dd, 1H, J=9 Hz, 4 Hz), 3.32 (s, 3H), 3.15 (m,2H)2.29 (s, 3H), 2.24 (s, 3H), 2.16 (s, 3H), 2.06 (s, 6H), 1.78-1.97 (m,4H) ppm.

EXAMPLE 318[2-(4-Chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(tetrahydro-furan-3-yl)-amine

[0627] 1H NMR(CDCl₃) d 7.04(s,2H), 6.11(s,1H), 4.27(brs,1H),3.7-4.1(m,4H), 2.2-2.4(m,1H0, 2.08(s,6H), 2.07(s,6H),1.94(m,1H) ppm.

EXAMPLE 319[1-(tert-Butyl-dimethyl-silanyloxymethyl)-propyl]-[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-amine

[0628] 1H NMR(CDCl₃) d 6.85(s, 2H), 6.07( s, 1H), 3.71(m, 2H), 3.39(m,1H), 2.28(s, 3H), 2.16(s, 3H), 2.09(s, 3H), 2.06(s, 6H), 1.70(m, 2H),0.91(s 9H)ppm

EXAMPLE 320[3,6-Dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-ethyl-(2-pyrrolidin-1-yl-ethyl)-amine

[0629] 1H NMR(CDCl₃) d 6.86 (s, 2H), 6.44 (s, 1H), 3.25-3.30 (m, 2H),3.12 (q, 2H, J=7 Hz), 2.56-2.66 (m, 6H), 2.29 (s, 3H), 2.23 (s, 3H),2.17 (s, 3H), 2.05 (s, 6H), 1.80 (br s, 4H), 1.09 (t, 3H, J=7 Hz)

[0630] 13C NMR(CDCl₃) d.

[0631] APCI+m/z=382(M+1)

EXAMPLE 3214-[4-(1-Ethyl-propoxy)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-benzoicacid

[0632] To a −78° C. solution of intermediate in dry THF was addedn-BuLi. After stirring at that temperature for 10 min, CO₂(g) wasbubbled into the reaction mixture. The resulting mixture was stirred at−78° C. for 2 hr, gradually warmed to rt. The mixture was quenched withdilute HCl and extracted with methylene chloride. The organic layer wasseparated, dried, concentrated, and purified to give the title compoundas a white solid, mp. 168.4° C. 1H NMR(CDCl₃) 7.58(s,2H), 6.36(s,1H),4.24(m,1H), 2.35(s,3H), 2.22(s,3H), 2.14(s,6H), 1.75(m,4H), 0.99(t,6H)ppm.

[0633] The following Examples 322-326 were prepared according to thefollowing general procedure: To a solution of4-[4-(1-ethyl-propoxy)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-benzoicacid in anhydrous methylene chloride was added SOCl₂ and stirred at rt.for 1 hr. the mixture was concentrated to dryness to provide thecorresponding acyl chloride. The acyl chloride was quenched with anappropriate nucleophile (e.g., NH₃, MeNH₂, Me₂NH, EtNH₂, or methanol)and stirred at rt to provide the title compounds:

EXAMPLE 3224-[4-(1-Ethyl-propoxy)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-benzamide

[0634] 1H NMR(CDCl₃) d 7.51(s,2H), 6.32(s,1H), 6.2(brs,1H), 5.7(brs,1H),4.20(m,1H), 2.22(s,3H), 2.19(s,3H), 2.12(s,6H), 1.72(m,4H), 0.97(t,6H)ppm.

EXAMPLE 3234-[4-(1-Ethyl-propoxy)-3,6-dimethyl-pyridin-2-yloxy]-3,5,N-trimethyl-benzamide

[0635] 1H NMR(CDCl₃) d 7.43(s,2H), 6.30(s,1H), 6.19(brs,1H), 4.19(m,1H),2.95(d,3H), 2.19(s,3H), 2.18(s,3H), 2.10(s,6H), 1.71(m,4H), 0.97(t,6H)ppm.

EXAMPLE 3244-[4-(1-Ethyl-propoxy)-3,6-dimethyl-pyridin-2-yloxy]-3,5,N,N-tetramethyl-benzamide

[0636] 1H NMR(CDCl₃) d 7.12(s,2H), 6.30(s,1H), 4.18(m,1H), 3.09(s,3H),3.05(s,3H), 2.18(s,6H), 2.10(s,6H), 1.71(m,4H), 0.97(t,6H) ppm.

EXAMPLE 325N-Ethyl-4-[4-(1-ethyl-propoxy)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-benzamide

[0637] 1H NMR(CDCl₃) d 7.46(s,2H), 6.30(s,1H), 6.1(brs,1H), 4.19(m,1H),3.48(m,2H), 2.18(s,6H), 2.12(s,6H), 1.72(m,4H), 1.25(t,3H), 0.97(t,6H)ppm.

EXAMPLE 3264-[4-(1-Ethyl-propoxy)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-benzoicacid methyl ester

[0638] 1H NMR(CDCl₃) d 7.76(s,2H), 6.30(s,1H), 4.17(m,1H), 3.89(s,3H),2.19(s,3H), 2.169(s,3H), 2.12(s,6H), 1.712(m,4H), 0.97(t,6H) ppm.

[0639] The following Examples 327-329 were prepared by the followinggeneral procedure: To a solution of4-[4-(1-Ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-benzoicacid in anhydrous methylene chloride was added SOCl₂ and stirred at rtfor 1 hr. the mixture was concentrated to dryness to provide thecorresponding acyl chloride. The acyl chloride was quenched with anappropriate nucleophile (e.g., NH₃, MeNH₂, or methanol) and stirred atrt to provide the title compounds:

EXAMPLE 3274-[4-(1-Ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-benzamide

[0640] 1H NMR(CDCl₃) d 7.51(s,2H), 6.2(brs,1H), 6.1(s,1H), 5.5(brs,1H),3.9(d,1H), 3.3(m,1H), 2.19(s,3H), 2.14(s,6H), 2.12(s,3H), 1,7(m,2H),1.5(m,2H), 0.96(t,6H) ppm.

EXAMPLE 3284-[4-(1-Ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5,N-trimethyl-benzamide

[0641] 1H NMR(CDCl₃) d 7.431(s,2H), 6.3(ds,1H), 6.091(s,1H), 3.8(d,1H),3.35(m,1H), 2.96(d,3H), 2.16 (s,3H), 2.12(s,9H), 1.65(m,2H), 1.53(m,2H),0.95(t,6H) ppm.

EXAMPLE 3294-[4-(1-Ethyl-propylamino)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-benzoicacid methyl ester

[0642] 1H NMR(CDCl₃) d 7.751(s,2H), 6.08(s,1H), 3.89(s,3H), 3.80(d,1H),3.34(m,1H), 2.13(s,6H), 2.11(s,6H), 1.66(m,2H), 1.54(m,2H), 0.95(t,6H)ppm.

[0643] The following Examples 330-340 relate to other compounds offormula I of the invention, wherein R₄ is —CN:

EXAMPLE 3302-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-4-(tetrahydro-furan-3-ylamino)-nicotinonitrile

[0644] APCI [M+1]358.3

EXAMPLE 3314-(1-Ethyl-propylamino)-2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-nicotinonitrile

[0645] Cala: C: 71.36; H: 7.70; N:11.89; found: C: 71.16, H: 8.09, N:11.47; HNMR(CDCl:₃) 6.59(s, 2H), 6.08(s, 1H), 4.74(d, 1H), 3.78(s, 3H),3.38(m, 1H), 2.18(s, 3H), 2.10(s, 6H), 1.64(m, 2H), 1.55(m, 2H), 0.96(t,6H)ppm.

EXAMPLE 3324-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-pyridin-3-yloxy)-nicotinonitrile

[0646] The title compound was prepared by heating2-chloro-4-(1-ethyl-propylamino)-6-methyl-nicotinonitrile with2,4,6-trimethyl-3-hydroxy-pyridine in NMP.

[0647] 1HNMR(CDCl₃) 7.02(m,1H), 6.13(s, 1H), 4.81(d, 1H),3.40(m, 1H0,2.67(s, 3H0, 2.48(s, 3H0, 2.25(s, 3H), 2.16(s, 3H), 1.68(m, 4H), 0.97(t,6H)ppm

EXAMPLE 3332-(4-Methoxy-2,6-dimethyl-phenoxy)-4-(1-methoxymethyl-propylamino)-6-methyl-nicotinonitrile

[0648] 1HNMR(CDCl₃) 6.59(s, 2H), 6.11(s, 1H), 5.08(d, 1H), 3.78(s, 3H),3.56(m, 1H), 3.47(m, 1H), 3.38(s, 3H), 2.19(s, 3H), 2.10(s, 6H), 1.61(m,2H), 0.99(t, 3H) ppm

EXAMPLE 3342-(4-Bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-nicotinonitrile

[0649] 1H NMR(CDCl₃) d 7.19(s,2H), 6.09(s,1H), 4.77(d,1H), 3.39(m,1H),2.18(s,3H), 2.10(s,6H), 1.65(m,2H), 1.55(m,2H), 0.96(t,3H) ppm.

EXAMPLE 3354-[3-Cyano-4-(1-ethyl-propylamino)-6-methyl-pyridin-2-yloxy]-3-methoxy-benzoicacid methyl ester

[0650] APCl [M+1]384.2, 1H NMR(CDCl₃)

EXAMPLE 3364-[3-Cyano-4-(1-ethyl-propylamino)-6-methyl-pyridin-2-yloxy]-3-methoxy-benzamide

[0651] 1H NMR(CDCl₃) d 7.52(s,1H), 7.32(d,1H), 7.16(d,1H), 6.25(brs,1H),6.12(s,1H), 5.8(brs,1H), 4.78(d,1H), 3.80(s,3H), 3.39(m,1H), 2.20(s,3H),1.67(m,2H), 1.55(m,2H), 0.95(t,3H) ppm.

EXAMPLE 3372-(4-Chloro-2,6-dimethyl-phenoxy)-4-(1-methoxymethyl-propylamino)-6-methyl-nicotinonitrile

[0652] 1H NMR(CDCl₃) d 7.03(s,2H), 6.12(s,1H), 5.08(d,1H), 3.47(m,1H),3.43(m,2H), 3.38(s,3H), 2.18(s,3H), 2.09(s,6H), 1.76(m,2H), 1.61 (m,2H),0.99(t,6H) ppm.

EXAMPLE 3382-(4-Chloro-2,6-dimethyl-phenoxy)-4-[(1-methoxymethyl-propyl)-methyl-amino]-6-methyl-nicotinonitrile

[0653] 1H NMR(CDCl₃) d 7.03(s,2H), 6.27(s,1H), 4.33(m,1H), 3.59(m,1H),3.52(m,1H), 3.35(s,3H), 3.06(s,3H), 2.16(s,3H), 2.11 (s,6H), 1.69(m,4H),0.97(t,6H) ppm.

EXAMPLE 3392-(4-Chloro-2-methoxy-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-nicotinonitrile

[0654] 1H NMR(CDCl₃) d 7.04 (d, 1H, J=9 Hz), 6.91-6.94 (m, 2H), 6.10 (s,1H), 4.73 (d, 1H, J=9 Hz), 3.75 (s, 3H), 3.35-3.38 (m, 1H), 2.19 (s,3H), 1.47-1.70 (m, 4H), 0.95 (t, 6H, J=8 Hz) APCI+m/z=360.1 (M+1), 362.1(M+3)

EXAMPLE 3402-(4-Bromo-2-methoxy-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-nicotinonitrile

[0655] 1H NMR(CDCl₃) d 7.06-7.09 (m, 2H), 6.98-7.00 (m, 1H), 6.10 (s,1H), 4.73 (br d, 1H), 3.75 (s, 3H), 3.35-3.42 (m, 1H), 2.21 (s, 3H),1.43-1.72 (m, 4H), 0.95(t, 6H, J=7 Hz) ppm.

[0656] Other examples of compounds of the invention are as follows:

EXAMPLE 341[2-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-yl]-(1-methoxymethyl-propyl)-amine

[0657] 1H NMR(CDCl₃) d 7.05 (s, 2H), 6.04 (s, 1H), 5.33 (s, 1H), 4.26(br d, 1H), 3.34-3.39 (m, 1H), 3.31 (s, 6H), 2.31 (s, 3H), 2.12 (s, 6H),1.47-1.61 (m, 4H), 0.89 (t, 6H, J=8 Hz) ppm.

EXAMPLE 342[2-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-3-methylaminomethyl-pyridin-4-yl]-(tetrahydro-furan-3-yl)-amine

[0658] 1H NMR(CDCl₃) d 7.03(s,2H), 6.08(s,1 H), 4.18(s,2H),3.8-4.2(m,5H), 2.57(s,3H), 2.2-2.4(m,2H), 2.15(s,3H), 2.04(s,6H) ppm.

EXAMPLE 343[2-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-4-(tetrahydro-furan-3-ylamino)-pyridin-3-yl]-methanol

[0659] 1H NMR(CDCl₃) d 7.02(s,2H), 6.10(s,1H), 5.49(brs,1H), 4.89(t,2H),4.12(brs,1H), 4.01(m,2H), 3.99(m,1H), 3.75(m,1H), 2.30(m,1 H),2.16(s,3H), 2.05(s,6H), 1.95(m,1H) ppm.

EXAMPLE 3442-[2-(4-Chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-4-ylamino]-4-methylsulfanyl-butan-1-ol

[0660] 1H NMR(CDCl₃) d 7.06(s,2H), 6.29(s,1H), 5.47(s,1H),3.6-3.8(m,2H), 3.5(m,1H), 2.38(s,3H), 2.11(s,6H), 2.03(s,3H),1.87(m,1H), 1.69(m,1H) ppm.

PREPARATION A(6-Chloro-2-methyl-5-nitro-pyrimidin-4-yl)-(2,4,6-trimethyl-pyridin-3-yl)-amine

[0661] A solution of 2-methyl-5-nitro-4,6-dichloro-pyrimidine (208 mg,1.00 mmol) in 2.5 ml of acetonitrile was treated with2,4,6-trimethyl-3-amino-pyridine (273 mg, 2 mmol) stirred at roomtemperature 2 hours. The mixture was quenched with water and extractedwith ethyl acetate. The organic layer was washed with brine, dried andconcentrated to give red residue. The residue was purified throughsilica gel column chromatography using chloroform to 6% methanol inchloroform as eluent to give the title compound (110 mg, 36%) as anorange oil. ¹H NMR (CDCl₃) δ 8.78 (brs, 1H), 6.97 (s, 1H), 2.54 (s, 3H),2.43 (s, 3H), 2.40 (s, 3H), 2.17 (s, 3H) ppm.

PREPARATION B 2-Chloro-4-(1-ethyl-propylamino)-6-methyl-nicotinic acid

[0662] The title compound was prepared by reaction of2-chloro-4-(1-ethyl-propylamino)-6-methyl-nicotinic acid methyl esterwith LiOH.H₂O in a mixture of water and dioxane at room temperature. Thedesired product was acidified to pH 3 and extracted with ethyl acetate.The organic layer was dried and concentrated to dryness. The titlecompound was obtained as white crystals after titration with ethylacetate. mp. 164-165° C.; anal. For C₁₂H₁₇Cl₂O₂ cacl. C, 56.14; H, 6.67;N, 10.91; found: C, 56.40; H, 6.53; H, 10.93.

PREPARATION C4-Chloro-6-ethyl-3-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine 1-oxide

[0663] To a solution of 2,4,6-trimethylphenol in dry THF was added NaHand stirred at room temperature for 20 minutes. A solution of2,4-dichloro-6-ethyl-3-methyl-pyridine 1-oxide was added and theresulting mixture was heated at reflux for 1.5 hour. The mixture wascooled to room temperature, quenched with water, extracted with ethylacetate. The organic layer was separated, dried and concentrated to givethe title compound which was used directly for the next step reaction.

PREPARATION D4-Chloro-6-ethyl-3-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine

[0664] To a solution of4-Chloro-6-ethyl-3-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine 1-oxidein methylene chloride was added PCl₃ and the resulting mixture washeated at reflux for 20 min, cooled to rt. The mixture was concentratedto dryness. The residue was worked-up using standard procedure to givethe title compound. After silica gel purification, the titel compoundwas prepared as a white solid, mp. 42-44° C. Anal. For C₁₇H₂₀ClNO calc.C, 70.46; H, 6.96; N, 4.83; found, C, 70.35; H, 7.13; N, 4.58.

PREPARATION E2-[4-Chloro-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-ylmethyl]-malonicacid dimethyl ester

[0665] The title compound was prepared by reacting4-chloro-3-chloromethyl-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridinewith dimethyl malonate/NaH in methanol. The title compound was isolatedas a colorless oil.

PREPARATION F4-Chloro-3,6-dimethyl-2-(2,4,6-trimethyl-3-pyridyl)-pyridine PREPARATIONG 2-Chloro-4-(1-methoxymethyl-propoxy)-6-methyl-nicotinic acid ethylester

[0666] 1H NMR(CDCl₃) d 6.72(s,1H), 4.5(m,1H), 4.4(q,2H), 3.49(d,2H),3.31(s,3H), 2.46(s,3H), 1.68(m,2H), 1.34(t,3H), 0.93(t,3H) ppm.

PREPARATION H 2-Chloro-4-(1-methoxymethyl-propoxy)-6-methyl-nicotinicacid

[0667] 1H NMR(CDCl₃) d 6.81(s,2H), 4.51(m,1H), 3.60(m,2H), 3.40(s,3H),2.55(s,3H), 1.77(m,2H), 1.02(t,3H)ppm.

PREPARATION I(2-Chloro-6-methyl-3-nitro-pyridin-4-yl)-(1-methoxymethyl-propyl)-amine

[0668] mp. 63-65° C., Anal. For C₁₁H16N3O3Cl calc. C, 48.27; H, 5.89, N,15.35; found C, 48.65; H, 6.03, N, 15.11.

PREPARATION J (5-Bromo-6-chloro-2-methyl-pyrimidin-4-yl)-(2,4-dichloro-phenyl )-amine

[0669] Mp. 165-167° C.; Anal. For C11H7BrCl3 caic.: C, 35.95; H, 1.92;N, 11.43; found: C, 36.41; H, 1.91; N, 11.05.

PREPARATION K(6-Chloro-2-methyl-pyrimidin-4-yl)-(2,4-dichloro-phenyl)-amine

[0670] Mp. 134-136° C.; Anal. For C₁₁H₈Cl₃N₃ calc.: C, 45.79; H, 2.79;N, 14.56; found: C, 45.91; H, 2.69; N, 14.50.

PREPARATION L[4-Chloro-6-(1-ethyl-propylamino)-2-methyl-pyrimidin-5-yl]-acetic acidethyl ester

[0671] Mp. 78-80° C., anal. For C₁₄H₂₂ClN₃O₂ calc.: C, 56.09; H, 7.40;N, 14.02; found: C, 56.31; H, 7.60; N,13.94.

PREPARATION M2-[4-Bromo-2-methyl-6-(2,4,6-trimethyl-phenoxy)-pyrimidin-5-yl]-propionicacid ethyl ester

[0672] 1H NMR(CDCl₃) d 6.86(s,2H), 4.2-4.359m,2H), 4.0-4.15(m,1H),2.4(s,3H), 2.28(s,3H), 1.99(s,3H), 1.97(s,3H), 1.58(d,3H), 1.22(t,3H)ppm.

PREPARATION N 2-(4,6-Dibromo-2-methyl-pyrimidin-5-yl)-propionic acidethyl ester

[0673] 1H NMR(CDCL₃) 4.36(m,1H), 4.19(m,2H), 2.68(s,3H), 1.549d,3H),1.22(t,3H) ppm.

PREPARATION O4-Bromo-3-methoxy-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine

[0674] 1H NMR(CDCl₃) d 6.92(s,1H), 6.87(s,2H), 4.00(s,3H), 2.299s,3H),2.18(s,3H), 2.059s,6H) ppm.

PREPARATION P4-Bromo-2-(4-chloro-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridine

[0675] 1H NMR(CDCl₃) d 7.04(s,2H), 6.97(s,1 H), 2.42(s,3H), 2.17(s,3H),2.03(s,6H) ppm.

PREPARATION Q4-Bromo-2-(2,4-dichloro-6-methyl-phenoxy)-3-methoxy-6-methyl-pyridine

[0676] 1H NMR(CDCl₃) d 7.3(d,1H), 7.18(d,1H), 4.0(s,3H), 2.2(s,3H),2.15(s,3H) ppm.

PREPARATION R4-Bromo-2-(4-chloro-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridine

[0677] Anal. For C₁₅H₁₅BrClNO₂calc.: C, 50.52; H, 4.24; N, 3.93; found:C, 50.52; H, 4.37; N, 3.91.

PREPARATION S4-Bromo-2-(4-chloro-2-methoxy-phenoxy)-3-methoxy-6-methyl-pyridine

[0678] 1H NMR(CDCl₃) d 6.9-7.1(m,4H), 3.94(s,3H), 3.71(s,3H), 2.21s,3H)ppm.

PREPARATION T4-Bromo-2-(3-chloro-2,6-dimethoxy-phenoxy)-3-methoxy-6-methyl-pyridine

[0679] 1H NMR(CDCl₃) d 7.17(d,1H), 6.96(s,1H), 6.66(d,1H), 3.97(s,3H),3.79(s,3H), 3.70(s,3H), 2.18(s,3H) ppm.

PREPARATION U4-Bromo-3-methoxy-6-methyl-2-(2,4,6-trimethoxy-phenoxy)-pyridine

[0680] 1H NMR(CDCl₃) d 6.90(s,1H), 6.19(s,2H), 3.968(s,3H), 3.80(s,3H),3.71(s,6H), 2.18(s,3H) ppm.

PREPARATION V4-Bromo-3-methoxy-2-(4-methoxy-2,6-dimethyl-phenoxy)-6-methyl-pyridine

[0681] 1H NMR(CDCl₃) d 6.92(s,1H), 6.60(s,2H), 3.98(s,3H), 3.78(s,3H),2.18(s,3H), 2.07(s,6H) ppm.

PREPARATION W4-Bromo-2-(4-chloro-2,6-dimethyl-phenoxy)-3-ethoxy-6-methyl-pyridine

[0682] 1H NMR(CDCl₃) d 7.099s,2H), 7.00(s,1H), 4.28(q,2H), 2.22(s,3H),2.10(s,6H), 1.51(t,3H) ppm.

PREPARATION X 4-Bromo-3,6-dimethyl-2-(2,4,6-trimethoxy-phenoxy)-pyridine

[0683] 1H NMR(CDCl₃) d 6.99(s,1H), 6.25(s,2H), 3.86(s,3H), 3.77(s,6H),2.47(s,3H), 2.25(s,3H) ppm.

PREPARATION Y4-Chloro-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-1-oxy-nicotinic acidmethyl ester PREPARATION RR4-Chloro-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-nicotinic acidmethyl ester

[0684] 1H NMR(CDCl₃) d 7.03(s,2H), 6.869s,1H), 3.969s,3H), 2.259s,3H),2.05(s,6H) ppm.

PREPARATION Z4-Chloro-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridine-3-carbaldehyde

[0685] The title compound was prepared by oxidation of4-chloro-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl-methanol withpyridinium chlorochromate in methylene chloride at room temperature. Thedesired product was isolated after column chromatography to give a greensolid (80% yield). 1H NMR(CDCl₃) d 10.66(s,1H), 6.91(s,3H), 2.31(s,3H),2.07(s,3H) ppm.

PREPARATION M2-(4-Bromo-2,6-dimethyl-phenoxy)-4-chloro-6-methyl-nicotinic acid methylester

[0686] mp. 108-110° C.; Anal. For C₁₆H₁₅BrClNO₃ calc., 49.96; H, 3.93;N, 3.64; found: C, 50.07; H, 4.10; N, 3.57.

PREPARATION BB4-Chloro-2-(4-chloro-2-methoxy-phenoxy)-6-methyl-1-oxy-nicotinic acidmethyl ester

[0687] mp. 117-120° C., Anal. For C₁₅H₁₃NO₅Cl₂ calc.: C, 50.30; H, 3.66;N, 3.91; Found: C, 50.41; H, 3.55; N, 4.00.

PREPARATION CC4-Chloro-2-(4-chloro-2-methoxy-phenoxy)-6-methyl-nicotinic acid methylester

[0688] mp. 92-93° C., Anal. For C₁₅H₁₃NO₄Cl₂ calc.: C, 52.65; H, 3.83;N, 4.09; found: C, 52.34; H, 3.85; N, 4.13.

PREPARATION DD[1-(tert-Butyl-dimethyl-silanyloxymethyl)-propyl]-[2-(4-chloro-2,6-dimethy-phenoxy)-3,6-dimethyl-pyridin-4-yl]-amine

[0689] 1H NMR(CDCl₃) d 7.06(s,2H), 6.12(s,1H), 4.3(d,IH), 3.6-3.8(m,2H),3.4(m,1H), 2.16(s,3H), 2.14(s,3H), 2.10(s,6H), 1.5-1.8(m,2H),1.03(t,3H), 0.95(s,9H), 0.09(m,6H) ppm.

[0690] The following compounds were prepared by a method analogous tothat described in Example 160, using an appropriate4-bromo-2-(substituted phenoxy)-6-alkyl or alkoxy-pyridine with1-(tert-Butyl-dimethyl-silanyloxymethyl)-propylamine.

PREPARATION EE[1-(tert-Butyl-dimethyl-silanyloxymethyl)-propyl]-[3-methoxy-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-(S)-yl]-amine

[0691] 1H NMR (CDCl₃) d 6.84(s,2H), 6.08(s,1H), 4. 8(d,1H), 3.88(s,3H),3.5-3.7(m,2H), 3.3(m,1H), 2.27(s,3H), 2.099s,3H), 2.07(s,6H),1.75(m,1H), 1.55(m,1H), 0.97(t,3h), 0.89(s,9H), 0.04(s,6H) ppm.

PREPARATION FF[1-(tert-Butyl-dimethyl-silanyloxymethyl)-propyl]-[2-(4-chloro-2,6-dimethyl-phenoxy)-3-methoxy-6-methyl-pyridin-4-yl]-amine

[0692] 1H NMR(CDCl₃) d 7.02(s,2H), 6.10(s,1H), 4.80(d,1H), 3.87(s,3H),3.6-3.7(m,2H), 3.30(m,1H), 2.09(s,3H), 2.08(s,6H), 1.75(m,1H),1.55(m,1H), 0.97(t,3H), 0.89(s,9H), 0.03(s,6H) ppm.

PREPARATION GG4-[1-(tert-Butyl-dimethyl-silanyloxymethyl)-propylamino]-2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-pyridin-3-ol

[0693] 1H NMR(CDCl₃) d 7.01 (s,2H), 6.15(s,1H), 4.46(d,1H), 3.7(m,1H),3.6(m,1H), 3.4(m,1H), 2.09(s,3H), 2.08(s,6H), 1.5-1.8(m,2H), 1.06(s,9H),0.98(t,3H), 0.24(s,6H) ppm.

PREPARATION HH[1-(tert-Butyl-dimethyl-silanyloxymethyl)-propyl]-[3-methoxy-6-methyl-2-(2,4,6-trimethoxy-phenoxy)-pyridin-4-yl]-amine

[0694] 1H NMR(CDCl₃) d 6.19(s,2H), 6.09(s,1H), 3.86(s,3H), 3.80(s,3H),3.73(s,6H), 3.3(m,1H), 2.16(s,3H), 1.75(m,1H), 1.5(m,1H), 0.95(t,3H),0.89(s,9H), 0.04(s,6H) ppm.

PREPARATION II4-{4-[1-(tert-Butyl-dimethyl-silanyloxymethyl)-propylamino]-3-methoxy-6-methyl-pyridin-2-yloxy}-3,5-dimethyl-benzonitrile

[0695] 1H NMR(CDCl₃) d 7.40(s,2H), 6.19(s,1H), 4.90(brs,1H), 3.87(s,3H),3.70(m,2H), 3.3(m,1H), 2.19(m,9H), 1.5-1.8(m,2H), 1.02(t,3H), 093(s,9H),0.09(s,6H) ppm.

1. A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein the dashed linesrepresent optional double bonds, with the proviso that when the dashedline in C═G represent a double bond, then the dashed line in N(R₆)═Cdoes not represent a double bond; and with the proviso that when thedashed line in N(R₆)═C represents a double bond, R₆ is absent in formulaIII and the dashed line in C═G does not represent a double bond; A is—CR₇ or N; B is —NR₁R₂, —CR₁R₂R₁₁, —C(═CR₂R₁₂)R₁, —NHCHR₁R₂, —OCHR₁R₂,—SCHR₁R₂, —CHR₂OR₁, —CHR₁OR₂, —CHR₂SR₁, —C(S)R₂, —C(O)R₂, —CHR₂NR₁R₂,—CHR₁NHR₂, —CHR₁N(CH₃)R₂, or —NR₁₂NR₁R₂; when the dashed line in C═Grepresents a double bond, then G is hydrogen, oxygen, sulfur, NH, orN(C₁-C₄ alkyl); when the dashed line in C═G does not represent a doublebond, then C═G is C(H)(NH₂), CH₂, —C(H)(methoxy), —C(H)(ethoxy),—C(H)(O(C₃-C₄ alkyl)), —C(H)(halo), —C(H)(trifluoromethoxy),—C(H)(methyl), —C(H)(ethyl), —C(H)(C₃-C₄ alkyl), —C(H)(S(C₁-C₄ alkyl)),—C(C₁-C₄ alkyl)(C₁-C₄ alkyl), cyclopropyl, —C(H)(cyclopropyl),thiomethoxy, —C(H)(NH₂), —C(H)(NHCH₃), —C(H)(N(CH₃)₂), or—C(H)(trifluoromethyl); wherein said cyclopropyl, methoxy, ethoxy, C₃-C₄alkyl, and C₁-C₄ alkyl groups of C═G may optionally be substituted byone OH, methoxy, or trifluoromethoxy, or may optionally be substitutedby from one to six fluoro atoms; Y is CH or N; Z is NH, O, S, —N(C₁-C₂alkyl), —NC(O)CF₃, or —C(R₁₃R₁₄), wherein R₁₃ and R₁₄ are each,independently, hydrogen, trifluoromethyl or methyl, or one of R₁₃ andR₁₄ is cyano and the other is hydrogen or methyl, or —C(R₁₃R₁₄) is acyclopropyl group, or Z is nitrogen or CH and forms a five or sixmembered heterocyclic ring fused with R₅, which ring optionallycomprises two or three further hetero members selected independentlyfrom oxygen, nitrogen, NR₁₂, and S(O)_(m), and optionally comprises fromone to three double bonds, and is optionally substituted with halo,C₁-C₄ alkyl, —O(C₁-C₄ alkyl), NH₂, NHCH₃, N(CH₃)₂, CF₃, or OCF₃, withthe proviso that said ring does not contain any —S—S—, —S—O—, —N—S—, or—O—O— bonds, and does not comprise more than two oxygen or S(O)_(m)heterologous members; R₁ is C(O)H, C(O)(C₁-C₈ alkyl), C(O)(C₁-C₆alkylene)(C₃-C₈ cycloalkyl), C(O)(C₃-C₈ cycloalkylene)(C₃-C₈cycloalkyl), C(O)(C₁-C₆ alkylene)(C₄-C₈ heterocycloalkyl), -C(O)(C₃-(C₈cycloalkylene)(C₄-C₈ heterocycloalkyl), C₁-C₆ alkyl, C₃-C₈ cycloalkyl,C₄-C₈ heterocycloalkyl, —(C₁-C₆ alkylene)(C₃-C₈ cycloalkyl), -(C₃-C₈cycloalkylene)(C₃-C₈ cycloalkyl), -(C₁-C₆ alkylene)(C₄-C₈heterocycloalkyl), —(C₃-C₈ cycloalkylene)(C₄-C₈ heterocycloalkyl), or—O—aryl, or —O—(C₁-C₆ alkylene)-aryl; wherein said aryl, C₄-C₈heterocycloalkyl, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkylene,and C₁-C₆ alkylene groups may each independently be optionallysubstituted with from one to six fluoro and may each independently beoptionally substituted with one or two substituents R₈ independentlyselected from the group consisting of C₁-C₄ alkyl, -C₃-C₈ cycloalkyl,hydroxy, chloro, bromo, iodo, CF₃, —O—(C₁-C₆alkyl), —O—(C₃-C₅cycloalkyl), —O—CO—(C₁-C₄ alkyl), —O—CO—NH(C₁-C₄ alkyl),—O—CO—N(R₂₄)(R₂₅), —N(R₂₄)(R₂₅), —S(C₁-C₄ alkyl), —S(C₃-C₅ cycloalkyl),—N(C₁-C₄alkyl)CO(C₁-C₄ alkyl), —NHCO(C₁-C₄ alkyl), —COO(C₁-C₄ alkyl),—CONH(C₁-C₄ alkyl), —CON(C₁-C₄ alkyl)(C₁-C₂ alkyl), CN, NO₂, —OSO₂(C₁-C₄alkyl), S⁺(C₁-C₆ alkyl)(C₁-C₂ alkyl)l, —SO(C₁-C₄ alkyl) and —SO₂(C₁-C₄alkyl); and wherein the C₁-C₆ alkyl, C₁-C₆ alkylene, C₅-C₈ cycloalkyl,C₅-C₈ cycloalkylene, and C₅-C₈ heterocycloalkyl moieties of R₁ mayoptionally independently contain from one to three double or triplebonds; and wherein the C₁-C₄ alkyl moieties and C₁-C₆ alkyl moieties ofR₈ can optionally independently be substituted with hydroxy, amino,C₁-C₄ alkyl, aryl, —CH₂-aryl, C₃-C₅ cycloalkyl, or —O—(C_(1+L-C) ₄alkyl), and can optionally independently be substituted with from one tosix fluoro, and can optionally contain one or two double or triplebonds; and wherein each heterocycloalkyl group of R₁ contains from oneto three heteromoieties selected from oxygen, S(O)m, nitrogen, and NR₁₂;R₂ is hydrogen, C₁-C₁₂ alkyl, C₃-C₈ cycloalkyl, C₄-C₈ heterocycloalkyl,—(C₁-C₆ alkylene)(C₃-C₈ cycloalkyl), —(C₃-C₈ cycloalkylene)(C₃-C₈cycloalkyl), —(C₁-C₆ alkylene)(C₄-C₃ heterocycloalkyl), —(C₃-C₈cycloalkylene)(C₄-C₈ heterocycloalkyl), aryl, —(C₁-C₆ alkylene)aryl, or—(C₃-C₈ cycloalkylene)(aryl); wherein each of the foregoing R₂ groupsmay optionally be substituted with from one to three substituentsindependently selected from chloro, fluoro, and C₁-C₆ alkyl, wherein oneof said one to three substituents can further be selected from bromo,iodo, C₁-C₆ alkoxy, —OH, —O—CO—(C₁-C₆ alkyl), —O—CO—N(C₁-C₄ alkyl)(C₁-C₂alkyl), —S(C₁-C₆ alkyl), —S(O)(C₁-C₆ alkyl), —S(O)₂(C₁-C₆ alkyl),S⁺(C₁-C₆ alkyl)(C₁-C₂ alkyl)l⁻, CN, and NO₂; and wherein the C₁-C₁₂alkyl, —(C₁-C₈ alkylene), —(C₅-C₈ cycloalkyl), —(C₅-C₈ cycloalkylene),and —(C₅-C₈ heterocycloalkyl) moieties of R₂ may optionallyindependently contain from one to three double or triple bonds; andwherein each heterocycloalkyl group of R₂ contains from one to threeheteromoieties selected from oxygen, S(O)_(m), nitrogen, and NR₁₂; orwhen R₁ and R₂ are as in —NHCHR₁R₂, —OCHR₁R₂, —SCHR₁R₂, —CHR₁R₂ or—NR₁R₂, R₁ and R₂ of B may form a saturated 5- to 8-membered ring whichmay optionally contain one or two double bonds and in which one or twoof the ring carbons may optionally be replaced by an oxygen, S(O)_(m),nitrogen or NR₁₂; and which carbocyclic ring can optionally besubstituted with from 1 to 3 substituents selected from the groupconsisting of hydroxy, C₁-C₄ alkyl, fluord, chloro, bromo, iodo, CF₃,—O—(C₁-C₄ alkyl), —O—CO—(C₁-C₄ alkyl), —O—CO—NH(C₁-C₄ alkyl),—O—CO—N(C₁-C₄ alkyl)(C₁-C₂ alkyl), —NH(C₁-C₄ alkyl), —N(C₁-C₂alkyl)(C₁-C₄ alkyl), —S(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)CO(C₁-C₄ alkyl),—NHCO(C₁-C₄ alkyl),—COO(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CON(C₁-C₄alkyl)(C₁-C₂ alkyl), CN, NO₂, —OSO₂(C₁-C₄ alkyl), —SO(C₁-C₄ alkyl), and—SO₂(C₁-C₄ alkyl), wherein one of said one to three substituents canfurther be selected from phenyl; R₃ is methyl, ethyl, fluoro, chloro,bromo, iodo, cyano, methoxy, OCF₃, NH₂, NH(C₁-C₂ alkyl), N(CH₃)₂,—NHCOCF₃, —NHCH₂CF₃, S(O)_(m)(C₁-C₄ alkyl), CONH₂, —CONHCH₃, CON(CH₃)₂,—CF₃, or CH₂OCH₃; R₄ is hydrogen, C₁-C₄ alkyl, C₃-C₅ cycloalkyl, —(C₁-C₄alkylene)(C₃-C₅ cycloalkyl), —(C₃-C₅ cycloalkylene)(C₃-C₅ cycloalkyl),cyano, fluoro, chloro, bromo, iodo, —OR₂₄, C₁-C₆ alkoxy, —O—(C₃-C₅cycloalkyl), —O—(C₁-C₄ alkylene)(C₃-C₅ cycloalkyl), —O—(C₃-C₅cycloalkylene)(C₃-C₅ cycloalkyl), —CH₂SC(S)O(C₁-C₄ alkyl), —CH₂OCF₃,CF₃, amino, nitro, —NR₂₄R₂₅, —(C₁-C₄ alkylene)—OR₂₄, —(C₁-C₄alkylene)Cl, —(C₁-C₄ alkylene)NR₂₄R₂₅, —NHCOR₂₄, —NHCONR₂₄R₂₅, —C=NOR₂₄,—NHNR₂₄R₂₅, —S(O)_(m)R₂₄, —C(O)R₂₄, —OC(O)R₂₄, —C(O)CN, —C(O)NR₂₄R₂₅,—C(O)NHNR₂₄R₂₅, and —COOR₂₄, wherein the alkyl and alkylene groups of R₄may optionally independently contain one or two double or triple bondsand may optionally independently be substituted with one or twosubstituents R₁₀ independently selected from hydroxy, amino, —NHCOCH₃,—NHCOCH₂Cl, —NH(C₁-C₂ alkyl), —N(C₁-C₂ alkyl)(C₁-C₂ alkyl), —COO(C₁-C₄alkyl), —COOH, —CO(C₁-C₄ alkyl), C₁-C₆ alkoxy, C₁-C₃ thioalkyl, cyanoand nitro, and with one to four substituents independently selected fromfluoro and chloro; R₅ is aryl or heteroaryl and is substituted with fromone to four substituents R₂₇ independently selected from halo, C₁-C₁₀alkyl, —(C₁-C₄ alkylene)(C₃-C₈ cycloalkyl), —(C₁C₄ alkylene)(C₄-C₈heterocycloalkyl), —(C₃-C₈ cycloalkyl), —(C₄-C₈ heterocycloalkyl),—(C₃-C₈ cycloalkylene)(C₃-C₈ cycloalkyl), —(C₃-C₈ cycloalkylene)(C₄-C₈heterocycloalkyl), C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, nitro, cyano,—NR₂₄R₂₅, —NR₂₄COR₂₅, —NR₂₄CO₂R₂₆, —COR₂₄, —OR₂₅, —CONR₂₄R₂₅,—CO(NOR₂₂)R₂₃, —CO₂R₂₆, —C=N(OR₂₂)R₂₃, and —S(O)_(m)R₂₃; wherein saidC₁-C₁₀ alkyl, C₃-C₈ cycloalkyl, (C₁-C₄ alkylene), (C₃-C₈ cycloalkyl),(C₃-C₈ cycloalkylene), and (C₄-C₈ heterocycloalkyl) groups can beoptionally substituted with from one to three substituents independentlyselected form C₁-C₄ alkyl, C₃-C₈ cycloalkyl, (C₁-C₄ alkylene)(C₃-C₈cycloalkyl), —(C₃-C₈ cycloalkylene)(C₃-C₈ cycloalkyl), C₁-C₄ haloalkyl,hydroxy, C₁-C₆ alkoxy, nitro halo, cyano, —NR₂₄R₂₅, —NR₂₄COR₂₅,NR₂₄CO₂R₂₆, —COR₂₄, —OR₂₅, —CONR₂₄R₂₅, CO₂R₂₆, —CO(NOR₂₂)R₂₅, and—S(O)mR₂₃; and wherein two adjacent substituents of the R₅ group canoptionally form a 5-7 membered ring, saturated or unsaturated, fused toR⁵, which ring optionally can contain one, two, or three heterologousmembers independently selected from O, S(O)_(m), and N, but not any—S—S—, —O—O—, —S—O—, or —N—S— bonds, and which ring is optionallysubstituted with C₁-C₄ alkyl, C₃-C₈ cycloalkyl, —(C₁-C₄ alkylene)(C₃-C₈cycloalkyl), —(C₃-C₈ cyloalkylene)(C₃-C₈ cycloalkyl), C₁-C₄ haloalkyl,nitro, halo, cyano —NR₂₄R₂₅, NR₂₄COR₂₅, NR₂₄CO₂R₂₆, —COR₂₄, —OR₂₅,—CONR₂₄R₂₅, CO₂R₂₆, —CO(NOR₂₆)R₂₅, or —S(O)_(m)R₂₃; wherein one of saidone to four optional substituents R₂₇ can further be selected from—SO₂NH(C₁-C₄ alkyl), —SO₂NH(C₁-C₄ alkylene)(C₃-C₈ cycloalkyl),—SO₂NH(C₃-C₈ cycloalkyl), —SO₂NH(C₃-C₈ cycloalkylene)(C₃-C₈ cycloalkyl),—SO₂N(C₁-C₄ alkyl)(C₁-C₂ alkyl), —SO₂NH₂, —NHSO₂(C₁-C₄ alkyl),—NHSO₂(C₃-C₈ cycloalkyl), —NHSO₂(C₁-C₄ alkylene)(C₃-C₈ cycloalkyl), and—NHSO₂(C₃-C₈ cycloalkylene)(C₃-C₈ cycloalkyl); and wherein the alkyl,and alkylene groups of R₅ may independently optionally contain onedouble or triple bond; R₆ is hydrogen, C₁-C₆ alkyl, C₃-C₈ cycloalkyl,—(C₁-C₆ alkylene)(C₃-C₈ cycloalkyl), or —(C₃-C₈ cycloalkylene)(C₃-C₈cycloalkyl), wherein said alkyl and cycloalkyl may optionally besubstituted with one hydroxy, methoxy, ethoxy or fluoro group; or,wherein the compound is a compound of formula II, R₆ and R₄ can togetherform an oxo (=O) group, or can be connected to form a 3-8 memberedcarbocyclic ring, optionally containing one to three double bonds, andoptionally containing one, two, or three heterologous ring membersselected from O, SO_(m), N, and NR₁₂, but not containing any —O—O—,—S—O—, —S—S—, or —N—S— bonds, and further optionally substituted withC₁-C₄ alkyl or C₃-C₆ cycloalkyl, wherein said C₁-C₄ alkyl substituentmay optionally contain one double or triple bond; R₇ is hydrogen,methyl, fluoro, chloro, bromo, iodo, cyano, hydroxy, —O(C₁-C₂ alkyl),—O(cyclopropyl), —COO(C₁-C₂ alkyl), —COO(C₃-C₈ cycloalkyl), —OCF₃, CF₃,—CH₂OH, or CH₂OCH₃; R₁₁ is hydrogen, hydroxy, fluoro, ethoxy, ormethoxy; R₁₂ is hydrogen or C₁-C₄ alkyl; R₁₆ and R₁₇ are each,independently, hydrogen, hydroxy, methyl, ethyl, methoxy, or ethoxy,except that R₁₆ and R₁₇ are not both methoxy or ethoxy; or R₁₆ and R₁₇together form an oxo (=O) group; or R₁₆ and R₁₇ are connected to form a3-8 membered carbocyclic ring, optionally containing one to three doublebonds, and optionally containing from one to three heterologous ringmembers selected from O, SO_(m), N, and NR₁₂, but not containing any—O—O—, —S—O—, —S—S—, or —N—S— bonds, and further optionally substitutedwith C₁-C₄ alkyl or C₃-C₆ cycloalkyl, wherein said C₁-C₄ alkylsubstituent may optionally contain one double or triple bond; R₂₂ isindependently at each occurrence selected from hydrogen, C₁-C₄ alkyl,C₁-C₄ haloalkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₈ cycloalkyl, (C₃-C₈cycloalkylene)(C₃-C₈ cycloalkyl), and (C₁-C₄ alkylene)(C₃-C₈cycloalkyl); R₂₃ is independently at each occurrence selected from C₁-C₄alkyl, C₁-C₄ haloalkyl, C₂-C₈ alkoxyalkyl, C₃-C₈ cycloalkyl, —(C₁-C₄alkylene)(C₃-C₈ cycloalkyl), —(C₃-C₈ cycloalkylene)(C₃-C₈ cycloalkyl),aryl, —(C₁-C₄ alkylene)aryl, piperidine, pyrrolidine, piperazine,N-methylpiperazine, morpholine, and thiomorpholine; R₂₄ and R₂₅ areindependently at each occurrence selected from hydrogen, —C₁-C₄ alkyl,C₁-C₄ haloalkyl, especially CF₃, —CHF₂, CF₂CF₃, or CH₂CF₃, —(C₁-C₄alkylene)OH, —(C₁-C₄ alkylene)—O—(C₁-C₄ alkyl), —(C₁-C₄alkylene)—O—(C₃-C₅ cycloalkyl), C₃-C₈ cycloalkyl, —(C₁-C₄alkylene)(C₃-C₈ cycloalkyl), —(C₃-C₈ cycloalkylene)(C₃-C₈ cycloalkyl),—C₄-C₈ heterocycloalkyl, —(C₁-C₄ alkylene)(C₄-C₈ heterocycloalkyl),—(C₃-C₈ cycloalkylene)(C₄-C₈ heterocycloalkyl), aryl, and —(C₁-C₄alkylene)(aryl), wherein the —C₄-C₈ heterocycloalkyl groups can eachindependently optionally be substituted with aryl, CH₂-aryl, or C₁-C₄alkyl, and can optionally contain one or two double or triple bonds; or,when R₂₄ and R₂₅ are as NR₂₄R₂₅, —C(O)NR₂₄R₂₅, —(C₁C₄ alkylene)NR₂₄R₂₅,or —NHCONR₂₄R₂₅, then NR₂₄R₂₅ may further optionally form a 4 to 8membered heterocyclic ring optionally containing one or two furtherhetero members independently selected from S(O)_(m), oxygen, nitrogen,and NR₁₂, and optionally containing from one to three double bonds; R₂₆is independently at each occurrence selected from C₁-C₄ alkyl, C₁-C₄haloalkyl, C₃-C8 cycloalkyl, —(C₁-C₄ alkylene)(C₃-C₈ cycloalkyl),-(C₃-C₈ cycloalkylene)(C₃-C₈ cycloalkyl), aryl, and —(C₁-C₄alkylene)(aryl); and wherein each m is independently zero, one, or two,with the proviso that heterocycloalkyl groups of the compound of formulaI, II, or III do not comprise any —S—S—, —S—O—, —N—S—, or —O—O— bonds,and do not comprise more than two oxygen or S(O)_(m) heterologousmembers.
 2. A compound according to claim 1, wherein R₄ is —NHCH₂CF₃,—CONHNH₂, —CONHNHCH₃, —OCF₃, fluoro, —OCHF₂, —OCH₂(C₃-C₅ cycloalkyl),—O—(C₃-C₅ cycloalkyl), SCH₂(C₃-C₅ cycloalkyl), —S(C₃-C₅ cycloalkyl),—OCH₃, —CH₃, —CH₂CH₃, chloro, bromo, —CF₃, —CH₂OH, —CH₂OCH₃, —CH₂OCF₃,—SCH₃, —S(O)CH₃, —S(O)₂CH₃, —C(O)CH₃, —NR₂₄R₂₅, —NO₂, —CH(OH)CH₃, or—CN.
 3. A compound according to claim 1, wherein R₄ is —C(O)NR₂₄R₂₅ or—C(O)NHNR₂₄R₂₅.
 4. A compound according to claim 1, wherein R₄ is—(C₁-C₄ alkylene)NR₂₄R₂₅.
 5. A compound according to claim 1, wherein R₄is —COOCH₃ or —COOCH₂CH₃.
 6. A compound of formula I according to claim1, wherein Z is O; B is NHCHR₁R₂, wherein R₁ is —C(O)H, —C(O)(C₁-C₆alkyl), or —C₁-C₆ alkyl, wherein said C₁-C₆ alkyl is optionallysubstituted with from one to six fluoro atoms or one or two R₈independently selected from —C₁-C₄ alkyl, hydroxy and —(C₁-C₆ alkyl),and wherein R₂ is —C₁-C₂ alkyl optionally containing from one to threedouble or triple bonds and optionally substituted with from one threesubstituents selected from fluoro and C₁-C6 alkyl; R₅ is phenyl, pyridylor pyrimidyl, substituted with two or three R₂₇ groups selected fromhalo, —(C₁-C₄ haloalkyl), —C(O)R₂₄, —OR₂₅, —C(O)NR₂₄R₂₅, and C₁-C₁₀alkyl which is optionally substituted with one to three substituents,preferably one substituent, selected from hydroxy, C₁-C₆ alkoxy, and—NR₂₄R₂₅; and R₄ is —C(O)NR₂₄R₂₅.
 7. A compound of formula I accordingto claim 1, wherein Z is C; B is —NHCHR₁R₂, wherein R₁ of —NHCHR₁R₂ is—C(O)H, —C(O)(C₁-C₆ alkyl), or —C₁-C₆ alkyl, wherein said C₁-C₆ alkyl isoptionally substituted with from one to six fluoro atoms or one or twoR₈ independently selected from —C₁-C₄ alkyl, hydroxy and -O-(CI-C₆alkyl), and wherein R₂ of —NHCHR₁R₂ is —C₁-C₁₂ alkyl optionallycontaining from one to three double or triple bonds and optionallysubstituted with from one three substituents selected from fluoro andC₁-C₆ alkyl; R₅ is phenyl, pyridyl or pyrimidyl, substituted with two orthree R₂₇ groups selected from halo, —(C₁-C₄ haloalkyl), —C(O)R₂₄,—OR₂₅, —C(O)NR₂₄R₂₅, and C₁-C₁₀ alkyl which is optionally substitutedwith one to three substituents, preferably one substituent, selectedfrom hydroxy, C₁-C₆ alkoxy, and —NR₂₄R₂₅; and R₄ is —NR₁R₂, wherein R₁of —NR₁R₂ is C₁-C₆ alkyl, C₃-C₈ cycloalkyl, or —(C₁-C₆ alkylene)(C₃-C₈cycloalkyl), and R₂ of —NR₁R₂ is C₁-C₁₂ alkyl optionally containing fromone to three double or triple bonds and optionally substituted with fromone three fluoro atoms.
 8. A compound according to claim 1 selectedfrom:2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6,N-dimethyl-nicotinamide;2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-methoxymethyl-propylamino)-6,N-dimethyl-nicotinamide;2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-methoxymethyl-propylamino)-6-methyl-nicotinamide;2-(4-bromo-2-methoxy-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-nicotinamide;2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-methoxy-propylamino)-6-methyl-nicotinamide;2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-ethyl-2-methoxy-propylamino)-6,N-dimethyl-nicotinamide;2-(4-chloro-2-trifluoromethoxy-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-nicotinamide;2-(4-chloro-2-trifluoromethoxy-phenoxy)-4-(1-ethyl-propylamino)-6-N-dimethyl-nicotinamide;2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1S,2R-1-ethyl-2-methoxy-propylamino)-6,N-dimethyl-nicotinamide;2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1S,2S-1-ethyl-2-methoxy-propylamino)-6 ,N-dimethyl-nicotinamide;2-(4-bromo-2-methoxy-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-nicotinonitrile;4-[4-(1-ethyl-propoxy)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-benzamide;2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-4-(1-methylsulfanylmethyl-propylamino)nicotinic acid methyl ester;2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-hydroxymethyl-propylamino)-6-methyl-nicotinicacid methyl ester; 2-(4-bromo-2,6-dimethyl-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-nicotinonitrile;2-(4-chloro-2-trifluoromethoxy-phenoxy)-4-(1-ethyl-propylamino)-6-methyl-nicotinicacid methyl ester; and2-(4-chloro-2,6-dimethyl-phenoxy)-6-methyl-4-(tetrahydro-furan-3-ylamino)-nicotinicacid methyl ester; and pharmaceutically acceptable salts thereof.
 9. Apharmaceutical composition for the treatment of (a) a disorder orcondition the treatment of which can be effected or facilitated byantagonizing CRF, including but not limited to disorders induced orfacilitated by CRF, or (b) a disorder or condition selected frominflammatory disorders such as rheumatoid arthritis and osteoarthritis,pain, asthma, psoriasis and allergies; generalized anxiety disorder;panic; phobias, including social phobia, agoraphobia, and specificphobias; obsessive-compulsive disorder; post-traumatic stress, disorder;sleep disorders induced by stress; pain perception such as fibromyalgia;moocd disorders such as depression, including major depression, singleepisode depression, recurrent depression, child abuse induceddepression, mood disorders associated with premenstrual syndrome, andpostpartum depression; dysthemia; bipolar disorders; cyclothymia;chronic fatigue syndrome; stress-induced headache; cancer; irritablebowel syndrome, Crohn's disease; spastic colon; post operative ileus;ulcer; diarrhea; stress-induced fever; human immunodeficiency virusinfections; neurodegenerative diseases such as Alzheimer's disease,Parkinson's disease and Huntington's disease; gastrointestinal diseases;eating disorders such as anorexia and bulimia nervosa; hemorrhagicstress; chemical dependencies or addictions, including dependencies oraddictions to alcohol, cocaine, heroin, benzodiazapines, or other drugs;drug or alcohol withdrawal symptoms; stress-induced psychotic episodes;euthyroid sick syndrome; syndrome of inappropriate antidiuretic hormone;obesity; infertility; head trauma; spinal cord trauma; ischemic neuronaldamage, including cerebral ischemia, for example cerebral hippocampalischemia; excitotoxic neuronal damage; epilepsy; stroke; immunedysfunctions including stress induced immune dysfunctions, includingporcine stress syndrome, bovine shipping fever, equine paroxysmalfibrillation, confinement dysfunction in chicken, sheering stress insheep, and human-animal interaction stress in dogs; muscular spasms;urinary incontinence; senile dementia of the Alzheimer's type;multiinfarct dementia; amyotrophic lateral sclerosis; hypertension;tachycardia; congestive heart failure; osteoporosis; premature birth;hypoglycemia, and Syndrome X in a mammal or bird, comprising an amountof a compound according to claim 1 that is effective in the treatment ofsuch disorder or condition, and a pharmaceutically acceptable carrier.10. A method for the treatment of (a) a disorder or condition thetreatment of which can be effected or facilitated by antagonizing CRF,including but not limited to disorders induced or facilitated by CRF, or(b) a disorder or condition selected from inflammatory disorders such asrheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis andallergies; generalized anxiety disorder; panic; phobias, includingsocial phobia, agoraphobia, and specific phobias; obsessive-compulsivedisorder; post-traumatic stress disorder; sleep disorders induced bystress; pain perception such as fibromyalgia; mood disorders such asdepression, including major depression, single episode depression,recurrent depression, child abuse induced depression, mood disordersassociated with premenstrual syndrome, and postpartum depression;dysthemia; bipolar disorders; cyclothymia; chronic fatigue syndrome;stress-induced headache; cancer; irritable bowel syndrome, Crohn'sdisease, spastic colon; post operative ileus; ulcer; diarrhea;stress-induced fever; human immunodeficiency virus infections;neurodegenerative diseases such as Alzheimer's disease, Parkinson'sdisease and Huntington's disease; gastrointestinal diseases; eatingdisorders such as anorexia and bulimia nervosa; hemorrhagic stress;chemical dependencies or addictions, including dependencies oraddictions to alcohol, cocaine, heroin, benzodiazapines, or other drugs;drug or alcohol withdrawal symptoms; stress-induced psychotic episodes;euthyroid sick syndrome; syndrome of inappropriate antidiuretic hormone;obesity; infertility; head trauma; spinal cord trauma; ischemic neuronaldamage, including cerebral ischemia, for example cerebral hippocampalischemia; excitotoxic neuronal damage; epilepsy; stroke; immunedysfunctions including stress induced immune dysfunctions, includingporcine stress syndrome, bovine shipping fever, equine paroxysmalfibrillation, confinement dysfunction in chicken, sheering stress insheep, and human-animal interaction stress in dogs; muscular spasms;urinary incontinence; senile dementia of the Alzheimer's type;multiinfarct dementia; amyotrophic lateral sclerosis; hypertension;tachycardia; congestive heart failure; osteoporosis; premature birth;hypoglycemia, and Syndrome X in a mammal or bird, comprisingadministering to a subject in need of said treatment an amount of acompound according to claim 1, that is effective in treating suchdisorder or condition.
 11. A method of treating a condition comprisingadministering a compound of claim 1 in an amount effective to treat saidcondition, wherein said condition is selected from the group consistingof: a) abnormal circadian rhythm; b) depression, further wherein asecond compound for treating depression is administered, said secondcompound for treating depression having an onset of action that isdelayed with respect to that of said CRF antagonist; and c) emesis. 12.The method of claim 11 wherein the condition is abnormal circadianrhythm, and the compound is combined with a second compound useful fortreating a sleep disorder.
 13. The method of claim 12, wherein saidsecond compound is selected from the group consisting of tachykininantagonists, agonists for GABA brain receptors, metalonergic compounds,GABA brain receptor agonists, 5HT₂ receptor antagonists, and D4 receptorbinding.
 14. The method of claim 11 wherein said condition isdepression, and wherein said second compound having delayed action fortreating depression is selected from the group consisting of selectiveserotonin reuptake inhibitors, tricyclic antidepressants, norepinephrineuptake inhibitors, lithium, bupropion, sertraline, fluoxetine,trazodone, and a tricyclic antidepressant selected from the groupconsisting of imipramine, amitriptyline, trimipramine, doxepin,desipramine, nortriptyline, protriptyline, amoxapine, clomipramine,maprotiline, and carbamazepine, and pharmaceutically acceptable saltsand esters of the above-recited compounds.
 15. The method claim 11wherein said condition is emesis, further comprising administering asecond compound for treating emesis.
 16. The method of claim 15 whereinsaid second compound for treating emesis is, selected from the groupconsisting of tachykinin antagonists, 5HT3 antagonists, GABA agonists,and substance P inhibitors.
 17. A pharmaceutical composition fortreating a condition comprising a compound of claim 1 in an amounteffective to treat said condition and a pharmaceutically acceptablecarrier, wherein said condition is selected from the group consistingof: a) abnormal circadian rhythm; b) depression, further wherein asecond compound for treating depression is administered, said secondcompound for treating depression having an onset of action that isdelayed with respect to that of said CRF antagonist; and c) emesis. 18.A pharmaceutical composition according to claim 17, wherein thecondition is abnormal circadian rhythm, and the compound is combinedwith a second compound useful for treating a sleep disorder.
 19. Apharmaceutical composition according to claim 18, wherein said secondcompound is selected from the group consisting of tachykininantagonists, agonists for GABA brain receptors, metalonergic compounds,GABA brain receptor agonists, 5HT₂ receptor antagonists, and D4 receptorbinding .
 20. A pharmaceutical composition according to claim 17 whereinsaid condition is depression, and wherein said second compound havingdelayed action for treating depression is selected from the groupconsisting of selective serotonin reuptake inhibitors, tricyclicantidepressants, norepinephrine uptake inhibitors, lithium, bupropion,sertraline, fluoxetine, trazodone, and a tricyclic antidepressantselected from the group consisting of imipramine, amitriptyline,trimipramine, doxepin, desipramine, nortriptyline, protriptyline,amoxapine, clomipramine, maprotiline, and carbamazepine, andpharmaceutically acceptable salts and esters of the above-recitedcompounds.
 21. A pharmaceutical composition according to claim 17wherein said condition is emesis, further comprising administering asecond compound for treating emesis.
 22. A pharmaceutical compositionaccording to claim 21 wherein said second compound for treating emesisis selected from the group consisting of tachykinin antagonists, 5HT3antagonists, GABA agonists, and substance P inhibitors.